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Myers N, Droz D, Rogers BW, Tran H, Flores KB, Chan C, Knechtle SJ, Jackson AM, Luo X, Chambers ET, McCarthy JM. Modeling BK Virus Infection in Renal Transplant Recipients. Viruses 2024; 17:50. [PMID: 39861837 PMCID: PMC11768487 DOI: 10.3390/v17010050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 12/17/2024] [Accepted: 12/27/2024] [Indexed: 01/27/2025] Open
Abstract
Kidney transplant recipients require a lifelong protocol of immunosuppressive therapy to prevent graft rejection. However, these same medications leave them susceptible to opportunistic infections. One pathogen of particular concern is human polyomavirus 1, also known as BK virus (BKPyV). This virus attacks kidney tubule epithelial cells and is a direct threat to the health of the graft. Current standard of care in BK virus-infected transplant recipients is reduction in immunosuppressant therapy, to allow the patient's immune system to control the virus. This requires a delicate balance; immune suppression must be strong enough to prevent rejection, yet weak enough to allow viral clearance. We seek to model viral and immune dynamics with the ultimate goal of applying optimal control methods to this problem. In this paper, we begin with a previously published model and make simplifying assumptions that reduce the number of parameters from 20 to 14. We calibrate our model using newly available patient data and a detailed sensitivity analysis. Numerical results for multiple patients are given to show that the newer model reflects observed dynamics well.
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Affiliation(s)
- Nicholas Myers
- Center for Research in Scientific Computation, Department of Mathematics, North Carolina State University, Raleigh, NC 27695, USA; (N.M.); (D.D.); (K.B.F.)
| | - Dana Droz
- Center for Research in Scientific Computation, Department of Mathematics, North Carolina State University, Raleigh, NC 27695, USA; (N.M.); (D.D.); (K.B.F.)
| | - Bruce W. Rogers
- Department of Surgery, Duke University, Durham, NC 27710, USA (S.J.K.); (A.M.J.); (E.T.C.)
- Duke Center for Human Systems Immunology, Duke University, Durham, NC 27701, USA; (C.C.); (J.M.M.)
| | - Hien Tran
- Center for Research in Scientific Computation, Department of Mathematics, North Carolina State University, Raleigh, NC 27695, USA; (N.M.); (D.D.); (K.B.F.)
| | - Kevin B. Flores
- Center for Research in Scientific Computation, Department of Mathematics, North Carolina State University, Raleigh, NC 27695, USA; (N.M.); (D.D.); (K.B.F.)
| | - Cliburn Chan
- Duke Center for Human Systems Immunology, Duke University, Durham, NC 27701, USA; (C.C.); (J.M.M.)
- Department of Biostatistics and Bioinformatics, Duke University, Durham, NC 27710, USA
| | - Stuart J. Knechtle
- Department of Surgery, Duke University, Durham, NC 27710, USA (S.J.K.); (A.M.J.); (E.T.C.)
| | - Annette M. Jackson
- Department of Surgery, Duke University, Durham, NC 27710, USA (S.J.K.); (A.M.J.); (E.T.C.)
| | - Xunrong Luo
- Department of Medicine, Duke University, Durham, NC 27710, USA;
| | - Eileen T. Chambers
- Department of Surgery, Duke University, Durham, NC 27710, USA (S.J.K.); (A.M.J.); (E.T.C.)
- Department of Pediatrics, Duke University, Durham, NC 27710, USA
| | - Janice M. McCarthy
- Duke Center for Human Systems Immunology, Duke University, Durham, NC 27701, USA; (C.C.); (J.M.M.)
- Department of Biostatistics and Bioinformatics, Duke University, Durham, NC 27710, USA
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Han P, Guo Y, Zhang W, Wang D, Wu Y, Li X, Zhu M. Single-Cell RNA-Sequencing Reveals Heterogeneity and Transcriptional Dynamics in Porcine Circulating CD8 + T Cells. Cells 2024; 13:692. [PMID: 38667307 PMCID: PMC11049515 DOI: 10.3390/cells13080692] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Revised: 04/05/2024] [Accepted: 04/10/2024] [Indexed: 04/28/2024] Open
Abstract
Pigs are the most important source of meat and valuable biomedical models. However, the porcine immune system, especially the heterogeneity of CD8 T cell subtypes, has not been fully characterized. Here, using single-cell RNA sequencing, we identified 14 major cell types from peripheral blood circulating cells of pigs and observed remarkable heterogeneity among CD8 T cell types. Upon re-clustering of CD8+ T cells, we defined four CD8 T cell subtypes and revealed their potential differentiation trajectories and transcriptomic differences among them. Additionally, we identified transcription factors with potential regulatory roles in maintaining CD8 T cell differentiation. The cell-cell communication analysis inferred an extensive interaction between CD8 T cells and other immune cells. Finally, cross-species analysis further identified species-specific and conserved cell types across different species. Overall, our study provides the first insight into the extensive functional heterogeneity and state transitions among porcine CD8 T cell subtypes in pig peripheral blood, complements the knowledge of porcine immunity, and enhances its potential as a biomedical model.
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Affiliation(s)
- Pingping Han
- Key Laboratory of Agricultural Animal Genetics, Breeding, and Reproduction of Ministry of Education, Huazhong Agricultural University, Wuhan 430070, China; (P.H.); (Y.G.); (W.Z.); (D.W.); (Y.W.); (X.L.)
| | - Yaping Guo
- Key Laboratory of Agricultural Animal Genetics, Breeding, and Reproduction of Ministry of Education, Huazhong Agricultural University, Wuhan 430070, China; (P.H.); (Y.G.); (W.Z.); (D.W.); (Y.W.); (X.L.)
| | - Wei Zhang
- Key Laboratory of Agricultural Animal Genetics, Breeding, and Reproduction of Ministry of Education, Huazhong Agricultural University, Wuhan 430070, China; (P.H.); (Y.G.); (W.Z.); (D.W.); (Y.W.); (X.L.)
| | - Daoyuan Wang
- Key Laboratory of Agricultural Animal Genetics, Breeding, and Reproduction of Ministry of Education, Huazhong Agricultural University, Wuhan 430070, China; (P.H.); (Y.G.); (W.Z.); (D.W.); (Y.W.); (X.L.)
| | - Yalan Wu
- Key Laboratory of Agricultural Animal Genetics, Breeding, and Reproduction of Ministry of Education, Huazhong Agricultural University, Wuhan 430070, China; (P.H.); (Y.G.); (W.Z.); (D.W.); (Y.W.); (X.L.)
| | - Xinyun Li
- Key Laboratory of Agricultural Animal Genetics, Breeding, and Reproduction of Ministry of Education, Huazhong Agricultural University, Wuhan 430070, China; (P.H.); (Y.G.); (W.Z.); (D.W.); (Y.W.); (X.L.)
- The Cooperative Innovation Center for Sustainable Pig Production, Huazhong Agricultural University, Wuhan 430070, China
| | - Mengjin Zhu
- Key Laboratory of Agricultural Animal Genetics, Breeding, and Reproduction of Ministry of Education, Huazhong Agricultural University, Wuhan 430070, China; (P.H.); (Y.G.); (W.Z.); (D.W.); (Y.W.); (X.L.)
- The Cooperative Innovation Center for Sustainable Pig Production, Huazhong Agricultural University, Wuhan 430070, China
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3
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Kirkwood L, Ingram-Sills L, Taylor MD, Malone E, Florida-James G. Immune Response of Elite Enduro Racers to Laboratory and Racing Environments: The Influence of Training Impulse and Vibration. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021; 18:ijerph18094603. [PMID: 33926145 PMCID: PMC8123624 DOI: 10.3390/ijerph18094603] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 04/23/2021] [Accepted: 04/24/2021] [Indexed: 12/12/2022]
Abstract
Introduction: Understanding the sport-specific immune response elicited during both training and competition is imperative to maximise athlete health and performance. Despite a growing population of professional enduro mountain bike athletes, little is known about the recovery of the immune system following enduro racing events. Methods: Nine international level elite enduro mountain bike athletes (age 24.3 ± 2.4 years, height 178.5 ± 8.7 cm, mass 76.5 ± 12.5 kg) completed a laboratory-based maximal exercise test (LAB) on a cycle ergometer and competed in an international mountain bike enduro race event (RACE). Blood samples were taken before, immediately after, and 1 h after LAB and before, 1 h after, and 17 h after RACE. Leukocyte subsets were enumerated using seven-colour flow cytometry. Lucia’s training impulse (LuTRIMP) and vibration exposure (VIB) were quantified during RACE. Results: Seven participants were included in the final analyses. There was a significant (p < 0.05) increase in neutrophil count alongside a reduction of cytotoxic lymphocyte cell subsets of both the innate (CD3−/CD56+ NK-cells and CD3−/CD56dim NK-cells) and adaptive (CD8+/CD62L−/CD45RA− T-cells and CD8+/CD27+/CD28− T-cells) components of the immune system one hour after RACE. All cell counts returned to baseline values 17 h afterwards (p > 0.05). Cell subset redistribution from pre- to post-one-hour time points (%Δpre-post1h) in cell subsets with potent effector functions (Neutrophils, CD3−/CD56+ NK-cells, CD8+/CD62L−/CD45RA− T-cells, CD8+/CD27+/CD28− T-cells, and CD3−/CD56dim/CD57− NK-cells) was significantly greater at RACE than LAB (p < 0.05). VIB was shown to be a superior predictor of %Δpre-post1h CD4+ T-cells, CD4+ early T-cells, CD4+ naïve T-cells, and NK cells as compared with LuTRIMP on its own (ΔR2 = 0.63 − 0.89, p < 0.05). Conclusions: The race event offers a greater challenge to the immune system than LAB, and potentially, whole body vibration is a key component of training load measurement in mountain bike applications.
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Affiliation(s)
- Lewis Kirkwood
- School of Applied Sciences, Edinburgh Napier University, Edinburgh EH11 4BN, UK; (L.I.-S.); (E.M.); (G.F.-J.)
- Mountain Bike Centre of Scotland, Peel Tower, Glentress EH45 8NB, UK
- Correspondence:
| | - Lesley Ingram-Sills
- School of Applied Sciences, Edinburgh Napier University, Edinburgh EH11 4BN, UK; (L.I.-S.); (E.M.); (G.F.-J.)
- Mountain Bike Centre of Scotland, Peel Tower, Glentress EH45 8NB, UK
| | - Mark Dunlop Taylor
- School of Engineering and the Built Environment, Edinburgh Napier University, Edinburgh EH10 5DT, UK;
| | - Eva Malone
- School of Applied Sciences, Edinburgh Napier University, Edinburgh EH11 4BN, UK; (L.I.-S.); (E.M.); (G.F.-J.)
| | - Geraint Florida-James
- School of Applied Sciences, Edinburgh Napier University, Edinburgh EH11 4BN, UK; (L.I.-S.); (E.M.); (G.F.-J.)
- Mountain Bike Centre of Scotland, Peel Tower, Glentress EH45 8NB, UK
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Sponaas AM, Waage A, Vandsemb EN, Misund K, Børset M, Sundan A, Slørdahl TS, Standal T. Bystander Memory T Cells and IMiD/Checkpoint Therapy in Multiple Myeloma: A Dangerous Tango? Front Immunol 2021; 12:636375. [PMID: 33679794 PMCID: PMC7928324 DOI: 10.3389/fimmu.2021.636375] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Accepted: 01/26/2021] [Indexed: 12/19/2022] Open
Abstract
In this review article we discuss the role of the memory T cells in multiple myeloma (MM) and how they may influence immune responses in patients that received immunomodulating drugs and check point therapy.
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Affiliation(s)
- Anne Marit Sponaas
- Department of Clinical and Molecular Medicine, Center for Myeloma Research, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
| | - Anders Waage
- Department of Clinical and Molecular Medicine, Center for Myeloma Research, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.,Department of Hematology, St.Olavs Hospital, Trondheim, Norway
| | - Esten N Vandsemb
- Department of Clinical and Molecular Medicine, Center for Myeloma Research, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
| | - Kristine Misund
- Department of Clinical and Molecular Medicine, Center for Myeloma Research, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
| | - Magne Børset
- Department of Clinical and Molecular Medicine, Center for Myeloma Research, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.,Department of Immunology and Transfusion Medicine, St.Olavs Hospital, Trondheim, Norway
| | - Anders Sundan
- Department of Clinical and Molecular Medicine, Center for Myeloma Research, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
| | - Tobias Schmidt Slørdahl
- Department of Clinical and Molecular Medicine, Center for Myeloma Research, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.,Department of Hematology, St.Olavs Hospital, Trondheim, Norway
| | - Therese Standal
- Department of Clinical and Molecular Medicine, Center for Myeloma Research, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.,Department of Clinical and Molecular Medicine, Center of Molecular Inflammation Research, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
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García-Bustos MF, González-Prieto G, Paniz-Mondolfi AE, Parodi C, Beckar J, Monroig S, Ramos F, Mora MC, Delgado-Noguera LA, Hashiguchi Y, Jaime D, Moreno S, Ruiz-Morales L, Lemir CG, Barrio A. Risk factors for antimony treatment failure in American Cutaneous Leishmaniasis in Northwestern-Argentina. PLoS Negl Trop Dis 2021; 15:e0009003. [PMID: 33497376 PMCID: PMC7864468 DOI: 10.1371/journal.pntd.0009003] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 02/05/2021] [Accepted: 11/23/2020] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND To date, there is no specific literature available on the determinants for therapeutic failure (TF) with meglumine antimoniate (MA) in Northwestern-Argentina. This study aimed to identify epidemiological, clinical, and treatment-related factors that could be involved in TF. METHODOLOGY/PRINCIPAL FINDINGS We performed a case-control study. Cases were represented by patients who showed TF after administration of the first course of MA treatment, whereas, controls were determined as patients who evolved towards healing after the first MA cycle received. Crude Odds Ratios and their corresponding 90% confidence intervals (CI) were calculated, and risk factors were then tested by multivariate analysis using logistic binary regression. Three hundred and eighty-four patients with a presumptive diagnosis of ACL were recruited, and 153 with a positive diagnosis were selected. We included in the study 71 patients, who underwent specific treatment with MA, presented complete data on response to treatment, and had a minimum post-treatment follow-up of 6 months in cutaneous leishmaniasis, and 12 months in mucosal leishmaniasis. Of these, 34 (47.9%) presented TF. In the initial analysis, TF was significantly associated with the geographical area of disease acquisition (p = 0.036), the presence of mucosal lesions (p = 0.042), the presence of concomitant skin and mucosal lesions (p = 0.002), and lesion age ≥ 6 months (p = 0.018). Risk factors influencing TF in the final multivariate model included the geographical area where the disease was acquired (adjusted Odd Ratio 8.062; 95% CI 1.914-33.959; p = 0.004), and lesion age ≥ 6 months (adjusted Odd Ratio 10.037; 95% CI 1.383-72.843; p = 0.023). CONCLUSIONS/SIGNIFICANCE The results of the present study suggest the existence of some risk factors linked to TF in Northwestern-Argentina, which deserve further investigation. Herein we recorded a high percentage of TF and we described clinical and epidemiological characteristics associated with TF that could be taken into account improving the clinical management of patients.
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Affiliation(s)
- María F. García-Bustos
- Instituto de Patología Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, Salta, Argentina
- Escuela Universitaria en Ciencias de la Salud, Universidad Católica de Salta, Salta, Argentina
- Facultad de Ciencias de la Salud, Universidad Nacional de Salta, Salta, Argentina
- * E-mail: (MFGB); (AB)
| | | | - Alberto E. Paniz-Mondolfi
- Instituto de Investigaciones Biomédicas IDB, Departamento de Enfermedades Infecciosas y Medicina Tropical, Laboratorio de Patología de Enfermedades Infecciosas, Clínica IDB Cabudare, Cabudare, Venezuela
| | - Cecilia Parodi
- Instituto de Patología Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, Salta, Argentina
| | - Josefina Beckar
- Servicio de Otorrinolaringología, Hospital San Bernardo, Salta, Argentina
| | - Sibila Monroig
- Servicio de Otorrinolaringología, Hospital Papa Francisco, Salta, Argentina
| | - Federico Ramos
- Instituto de Patología Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, Salta, Argentina
| | - María C. Mora
- Instituto de Patología Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, Salta, Argentina
| | - Lourdes A. Delgado-Noguera
- Leishmania Collaborative Network, Emerging Pathogens Division, The Venezuelan Science Incubator, Cabudare, Venezuela
- Decanato de Ciencias de la Salud, Universidad Centroccidental Lisandro Alvarado (UCLA), Barquisimeto, Venezuela
| | - Yoshihisa Hashiguchi
- Department of Parasitology, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan
| | - Daniela Jaime
- Servicio de Dermatología, Hospital Joaquín Castellanos, Güemes, Salta, Argentina
| | - Sonia Moreno
- Servicio de Dermatología, Hospital Señor del Milagro, Salta, Argentina
| | | | - César G. Lemir
- Servicio de Infectología, Hospital San Bernardo, Salta, Argentina
| | - Alejandra Barrio
- Facultad de Ciencias de la Salud, Universidad Nacional de Salta, Salta, Argentina
- * E-mail: (MFGB); (AB)
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6
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Piatosa B, Wolska-Kuśnierz B, Tkaczyk K, Heropolitanska-Pliszka E, Grycuk U, Wakulinska A, Gregorek H. T Lymphocytes in Patients With Nijmegen Breakage Syndrome Demonstrate Features of Exhaustion and Senescence in Flow Cytometric Evaluation of Maturation Pathway. Front Immunol 2020; 11:1319. [PMID: 32695108 PMCID: PMC7338427 DOI: 10.3389/fimmu.2020.01319] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Accepted: 05/26/2020] [Indexed: 01/10/2023] Open
Abstract
Patients with Nijmegen Breakage Syndrome (NBS) suffer from recurrent infections due to humoral and cellular immune deficiency. Despite low number of T lymphocytes and their maturation defect, the clinical manifestations of cell-mediated deficiency are not as severe as in case of patients with other types of combined immune deficiencies and similar T cell lymphopenia. In this study, multicolor flow cytometry was used for evaluation of peripheral T lymphocyte maturation according to the currently known differentiation pathway, in 46 patients with genetically confirmed NBS and 46 sex and age-matched controls. Evaluation of differential expression of CD27, CD31, CD45RA, CD95, and CD197 revealed existence of cell subsets so far not described in NBS patients. Although recent thymic emigrants and naïve T lymphocyte cell populations were significantly lower, the generation of antigen-primed T cells was similar or even greater in NBS patients than in healthy controls. Moreover, the senescent and exhausted T cell populations defined by expression of CD57, KLRG1, and PD1 were more numerous than in healthy people. Although this hypothesis needs further investigations, such properties might be related to an increased susceptibility to malignancy and milder clinical course than expected in view of T cell lymphopenia in patients with NBS.
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Affiliation(s)
- Barbara Piatosa
- Histocompatibility Laboratory, Children's Memorial Health Institute, Warsaw, Poland
| | | | - Katarzyna Tkaczyk
- Histocompatibility Laboratory, Children's Memorial Health Institute, Warsaw, Poland
| | | | - Urszula Grycuk
- Histocompatibility Laboratory, Children's Memorial Health Institute, Warsaw, Poland
| | - Anna Wakulinska
- Department of Oncology, Children's Memorial Health Institute, Warsaw, Poland
| | - Hanna Gregorek
- Department of Microbiology and Clinical Immunology, Children's Memorial Health Institute, Warsaw, Poland
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Perdomo-Celis F, Medina-Moreno S, Davis H, Bryant J, Taborda NA, Rugeles MT, Kottilil S, Zapata JC. High activation and skewed T cell differentiation are associated with low IL-17A levels in a hu-PBL-NSG-SGM3 mouse model of HIV infection. Clin Exp Immunol 2020; 200:185-198. [PMID: 31951011 DOI: 10.1111/cei.13416] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/06/2020] [Indexed: 12/15/2022] Open
Abstract
The humanized NOD/SCID/IL-2 receptor γ-chainnull (NSG) mouse model has been widely used for the study of HIV pathogenesis. Here, NSG mice with transgenic expression of human stem cell factor (SCF), granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-3 (NSG-SGM3) were injected with peripheral blood leukocytes (PBL mice) from two HIV-infected (HIV+ ) patients who were under anti-retroviral therapy (ART; referred as HIV+ mice) or one HIV-seronegative healthy volunteer (HIV- ). Such mice are either hu-PBL-NSG-SGM3 HIV+ or HIV- mice, depending on the source of PBL. The kinetics of HIV replication and T cell responses following engraftment were evaluated in peripheral blood and secondary lymphoid tissues. High HIV replication and low CD4 : CD8 ratios were observed in HIV+ mice in the absence of anti-retroviral therapy (ART). Consistent with high activation and skewed differentiation of T cells from the HIV-infected donor, HIV+ mice exhibited a higher T cell co-expression of human leukocyte antigen D-related (HLA-DR) and CD38 than HIV- mice, as well as a shifted differentiation to a CCR7- CD45RA+ terminal effector profile, even in the presence of ART. In addition, HIV replication and the activation/differentiation disturbances of T cells were associated with decreased plasma levels of IL-17A. Thus, this hu-PBL-NSG-SGM3 mouse model recapitulates some immune disturbances occurring in HIV-infected patients, underlying its potential use for studying pathogenic events during this infection.
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Affiliation(s)
- F Perdomo-Celis
- Grupo Inmunovirologia, Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia.,Institute of Human Virology, School of Medicine, University of Maryland, Baltimore, MD, USA
| | - S Medina-Moreno
- Institute of Human Virology, School of Medicine, University of Maryland, Baltimore, MD, USA
| | - H Davis
- Institute of Human Virology, School of Medicine, University of Maryland, Baltimore, MD, USA
| | - J Bryant
- Institute of Human Virology, School of Medicine, University of Maryland, Baltimore, MD, USA
| | - N A Taborda
- Grupo Inmunovirologia, Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia
| | - M T Rugeles
- Grupo Inmunovirologia, Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia
| | - S Kottilil
- Institute of Human Virology, School of Medicine, University of Maryland, Baltimore, MD, USA
| | - J C Zapata
- Institute of Human Virology, School of Medicine, University of Maryland, Baltimore, MD, USA
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8
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Blom K, Cuapio A, Sandberg JT, Varnaite R, Michaëlsson J, Björkström NK, Sandberg JK, Klingström J, Lindquist L, Gredmark Russ S, Ljunggren HG. Cell-Mediated Immune Responses and Immunopathogenesis of Human Tick-Borne Encephalitis Virus-Infection. Front Immunol 2018; 9:2174. [PMID: 30319632 PMCID: PMC6168641 DOI: 10.3389/fimmu.2018.02174] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Accepted: 09/03/2018] [Indexed: 12/15/2022] Open
Abstract
Tick-borne encephalitis virus (TBEV) is a flavivirus that belongs to the Flaviviridae family. TBEV is transmitted to humans primarily from infected ticks. The virus causes tick-borne encephalitis (TBE), an acute viral disease that affects the central nervous system (CNS). Infection can lead to acute neurological symptoms of significant severity due to meningitis or meningo(myelo)encephalitis. TBE can cause long-term suffering and has been recognized as an increasing public health problem. TBEV-affected areas currently include large parts of central and northern Europe as well as northern Asia. Infection with TBEV triggers a humoral as well as a cell-mediated immune response. In contrast to the well-characterized humoral antibody-mediated response, the cell-mediated immune responses elicited to natural TBEV-infection have been poorly characterized until recently. Here, we review recent progress in our understanding of the cell-mediated immune response to human TBEV-infection. A particular emphasis is devoted to studies of the response mediated by natural killer (NK) cells and CD8 T cells. The studies described include results revealing the temporal dynamics of the T cell- as well as NK cell-responses in relation to disease state and functional characterization of these cells. Additionally, we discuss specific immunopathological aspects of TBEV-infection in the CNS.
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Affiliation(s)
- Kim Blom
- Department of Medicine Huddinge, Center for Infectious Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Angelica Cuapio
- Department of Medicine Huddinge, Center for Infectious Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - J. Tyler Sandberg
- Department of Medicine Huddinge, Center for Infectious Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Renata Varnaite
- Department of Medicine Huddinge, Center for Infectious Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Jakob Michaëlsson
- Department of Medicine Huddinge, Center for Infectious Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Niklas K. Björkström
- Department of Medicine Huddinge, Center for Infectious Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Johan K. Sandberg
- Department of Medicine Huddinge, Center for Infectious Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Jonas Klingström
- Department of Medicine Huddinge, Center for Infectious Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Lars Lindquist
- Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden
- Unit of Infectious Diseases, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Sara Gredmark Russ
- Department of Medicine Huddinge, Center for Infectious Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
- Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden
| | - Hans-Gustaf Ljunggren
- Department of Medicine Huddinge, Center for Infectious Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
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9
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Elias G, Souquette A, Heynderickx S, De Meester I, Jansens H, Beutels P, Van Damme P, Smits E, Thomas PG, Van Tendeloo V, Ogunjimi B. Altered CD4 + T cell immunity in nurses occupationally exposed to viral pathogens. Clin Exp Immunol 2018; 194:192-204. [PMID: 30076783 DOI: 10.1111/cei.13193] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2018] [Revised: 07/17/2018] [Accepted: 07/30/2018] [Indexed: 01/21/2023] Open
Abstract
Pathogen exposure, including but not limited to herpesviruses, moulds the shape of the immune system, both at a basal state and in response to immune challenge. However, little is known about the impact of high exposure to other viruses on baseline immune signatures and how the immune system copes with repetitive exposures to maintain a balanced functionality. Here we investigated baseline immune signatures, including detailed T cell phenotyping, antigen-specific CD4+ and CD8+ T cell responses and cytokine profile in paediatric (PED) nurses, who have high occupational exposure to viral pathogens including varicella zoster virus (VZV) and respiratory viruses, and in neonatal intensive care unit (NICU) nurses, as a control group with infrequent occupational exposure. Our results show a lower CD4+ T cell response to two VZV proteins (IE62 and gE) and to tetanus toxoid (TT) in PED nurses who are cytomegalovirus (CMV)-seronegative, compared to CMV-seronegative NICU nurses, and that the decline might be more pronounced the more sustained the exposure. This decline might be due to an attrition of VZV- and TT-specific T cells as a result of the continuous pressure on the CD4+ T cell compartment. Moreover, our data suggest that the distinct T cell phenotypes known to be associated with CMV-seropositivity might be less prominent in PED nurses compared to NICU nurses, implying a plausible attenuating effect of occupational exposure on CMV-associated immunosenescence. Overall, this pilot study reveals an impact of occupational exposure to viral pathogens on CD4+ T cell immunity and supports further investigation in a larger cohort.
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Affiliation(s)
- G Elias
- Laboratory of Experimental Haematology, Vaccine and Infectious Disease Institute (VAXINFECTIO), University of Antwerp, Antwerp, Belgium.,Antwerp Unit for Data Analysis and Computation in Immunology and Sequencing (AUDACIS), University of Antwerp, Antwerp, Belgium
| | - A Souquette
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - S Heynderickx
- Laboratory of Experimental Haematology, Vaccine and Infectious Disease Institute (VAXINFECTIO), University of Antwerp, Antwerp, Belgium
| | - I De Meester
- Laboratory of Medical Biochemistry, Department of Pharmaceutical Sciences, University of Antwerp, Antwerp, Belgium
| | - H Jansens
- Department of Microbiology, Antwerp University Hospital, University of Antwerp, Edegem (Antwerp), Belgium
| | - P Beutels
- Centre for Health Economics Research and Modeling Infectious Diseases (CHERMID), Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, Belgium.,Antwerp Unit for Data Analysis and Computation in Immunology and Sequencing (AUDACIS), University of Antwerp, Antwerp, Belgium
| | - P Van Damme
- Antwerp Unit for Data Analysis and Computation in Immunology and Sequencing (AUDACIS), University of Antwerp, Antwerp, Belgium.,Centre for the Evaluation of Vaccination (CEV), Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, Belgium
| | - E Smits
- Laboratory of Experimental Haematology, Vaccine and Infectious Disease Institute (VAXINFECTIO), University of Antwerp, Antwerp, Belgium.,Antwerp Unit for Data Analysis and Computation in Immunology and Sequencing (AUDACIS), University of Antwerp, Antwerp, Belgium.,Center for Oncological Research (CORE), University of Antwerp, Antwerp, Belgium
| | - P G Thomas
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - V Van Tendeloo
- Laboratory of Experimental Haematology, Vaccine and Infectious Disease Institute (VAXINFECTIO), University of Antwerp, Antwerp, Belgium.,Antwerp Unit for Data Analysis and Computation in Immunology and Sequencing (AUDACIS), University of Antwerp, Antwerp, Belgium
| | - B Ogunjimi
- Laboratory of Experimental Haematology, Vaccine and Infectious Disease Institute (VAXINFECTIO), University of Antwerp, Antwerp, Belgium.,Centre for Health Economics Research and Modeling Infectious Diseases (CHERMID), Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, Belgium.,Antwerp Unit for Data Analysis and Computation in Immunology and Sequencing (AUDACIS), University of Antwerp, Antwerp, Belgium.,Department of Paediatrics, Antwerp University Hospital, Edegem, Belgium
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10
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van den Berg SPH, Wong A, Hendriks M, Jacobi RHJ, van Baarle D, van Beek J. Negative Effect of Age, but Not of Latent Cytomegalovirus Infection on the Antibody Response to a Novel Influenza Vaccine Strain in Healthy Adults. Front Immunol 2018; 9:82. [PMID: 29434600 PMCID: PMC5796903 DOI: 10.3389/fimmu.2018.00082] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2017] [Accepted: 01/11/2018] [Indexed: 01/15/2023] Open
Abstract
Older adults are more vulnerable to influenza virus infection and at higher risk for severe complications and influenza-related death compared to younger adults. Unfortunately, influenza vaccine responses tend to be impaired in older adults due to aging of the immune system (immunosenescence). Latent infection with cytomegalovirus (CMV) is assumed to enhance age-associated deleterious changes of the immune system. Although lower responses to influenza vaccination were reported in CMV-seropositive compared to CMV-seronegative adults and elderly, beneficial effects of CMV infection were observed as well. The lack of consensus in literature on the effect of latent CMV infection on influenza vaccination may be due to the presence of pre-existing immunity to influenza in these studies influencing the subsequent influenza vaccine response. We had the unique opportunity to evaluate the effect of age and latent CMV infection on the antibody response to the novel influenza H1N1pdm vaccine strain during the pandemic of 2009, thereby reducing the effect of pre-existing immunity on the vaccine-induced antibody response. This analysis was performed in a large study population (n = 263) in adults (18–52 years old). As a control, memory responses to the seasonal vaccination, including the same H1N1pdm and an H3N2 strain, were investigated in the subsequent season 2010–2011. With higher age, we found decreased antibody responses to the pandemic vaccination even within this age range, indicating signs of immunosenescence to this novel antigen in the study population. Using a generalized estimation equation regression model, adjusted for age, sex, and previous influenza vaccinations, we observed that CMV infection in contrast did not influence the influenza virus-specific antibody titer after H1N1pdm vaccination. Yet, we found higher residual protection rates (antibody level ≥40 hemagglutinin units (HAU)) in CMV-seropositive individuals than in CMV-seronegative individuals 6 months and 1 year after pandemic vaccination. In the subsequent season, no effect of age or CMV infection on seasonal influenza vaccine response was observed. In conclusion, we observed no evidence for CMV-induced impairment of antibody responses to a novel influenza strain vaccine in adults. If anything, our data suggest that there might be a beneficial effect of latent CMV infection on the protection rate after novel influenza vaccination.
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Affiliation(s)
- Sara P H van den Berg
- Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, Netherlands.,Laboratory of Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
| | - Albert Wong
- Department of Statistics, Informatics and Mathematical Modelling, National Institute for Public Health and the Environment, Bilthoven, Netherlands
| | - Marion Hendriks
- Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, Netherlands
| | - Ronald H J Jacobi
- Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, Netherlands
| | - Debbie van Baarle
- Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, Netherlands.,Laboratory of Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
| | - Josine van Beek
- Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, Netherlands
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11
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Patil VS, Madrigal A, Schmiedel BJ, Clarke J, O'Rourke P, de Silva AD, Harris E, Peters B, Seumois G, Weiskopf D, Sette A, Vijayanand P. Precursors of human CD4 + cytotoxic T lymphocytes identified by single-cell transcriptome analysis. Sci Immunol 2018; 3:eaan8664. [PMID: 29352091 PMCID: PMC5931334 DOI: 10.1126/sciimmunol.aan8664] [Citation(s) in RCA: 175] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2017] [Revised: 09/27/2017] [Accepted: 11/30/2017] [Indexed: 01/03/2023]
Abstract
CD4+ cytotoxic T lymphocytes (CD4-CTLs) have been reported to play a protective role in several viral infections. However, little is known in humans about the biology of CD4-CTL generation, their functional properties, and heterogeneity, especially in relation to other well-described CD4+ memory T cell subsets. We performed single-cell RNA sequencing in more than 9000 cells to unravel CD4-CTL heterogeneity, transcriptional profile, and clonality in humans. Single-cell differential gene expression analysis revealed a spectrum of known transcripts, including several linked to cytotoxic and costimulatory function that are expressed at higher levels in the TEMRA (effector memory T cells expressing CD45RA) subset, which is highly enriched for CD4-CTLs, compared with CD4+ T cells in the central memory (TCM) and effector memory (TEM) subsets. Simultaneous T cell antigen receptor (TCR) analysis in single cells and bulk subsets revealed that CD4-TEMRA cells show marked clonal expansion compared with TCM and TEM cells and that most of CD4-TEMRA were dengue virus (DENV)-specific in donors with previous DENV infection. The profile of CD4-TEMRA was highly heterogeneous across donors, with four distinct clusters identified by the single-cell analysis. We identified distinct clusters of CD4-CTL effector and precursor cells in the TEMRA subset; the precursor cells shared TCR clonotypes with CD4-CTL effectors and were distinguished by high expression of the interleukin-7 receptor. Our identification of a CD4-CTL precursor population may allow further investigation of how CD4-CTLs arise in humans and, thus, could provide insights into the mechanisms that may be used to generate durable and effective CD4-CTL immunity.
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Affiliation(s)
- Veena S Patil
- Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA
| | - Ariel Madrigal
- Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA
| | - Benjamin J Schmiedel
- Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA
| | - James Clarke
- Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA
- Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, UK
| | - Patrick O'Rourke
- Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA
| | - Aruna D de Silva
- Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA
- Genetech Research Institute, Colombo, Sri Lanka
| | - Eva Harris
- Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Bjoern Peters
- Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA
- Department of Medicine, University of California San Diego, 9500 Gilman Drive #0656, La Jolla, CA 92093, USA
| | - Gregory Seumois
- Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA
| | - Daniela Weiskopf
- Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA
| | - Alessandro Sette
- Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA
- Department of Medicine, University of California San Diego, 9500 Gilman Drive #0656, La Jolla, CA 92093, USA
| | - Pandurangan Vijayanand
- Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
- Department of Medicine, University of California San Diego, 9500 Gilman Drive #0656, La Jolla, CA 92093, USA
- Clinical and Experimental Sciences, Sir Henry Wellcome Laboratories, Faculty of Medicine University of Southampton, Southampton, UK
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12
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Nguyen TA, Kahn DA, Loewendorf AI. Maternal-Fetal rejection reactions are unconstrained in preeclamptic women. PLoS One 2017; 12:e0188250. [PMID: 29176779 PMCID: PMC5703473 DOI: 10.1371/journal.pone.0188250] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Accepted: 11/05/2017] [Indexed: 12/11/2022] Open
Abstract
The risk factors for preeclampsia, extremes of maternal age, changing paternity, concomitant maternal autoimmunity, and/or birth intervals greater than 5 years, suggest an underlying immunopathology. We used peripheral blood and lymphocytes from the UteroPlacental Interface (UPI) of 3rd trimester healthy pregnant women in multicolor flow cytometry-and in vitro suppression assays. The major end-point was the characterization of activation markers, and potential effector functions of different CD4-and CD8 subsets as well as T regulatory cells (Treg). We observed a significant shift of peripheral CD4 -and CD8- T cells from naïve to memory phenotype in preeclamptic women compared to healthy pregnant women consistent with long-standing immune activation. While the proportions of the highly suppressive Cytokine and Activated Treg were increased in preeclampsia, Treg tolerance toward fetal antigens was dysfunctional. Thus, our observations indicate a long-standing inflammatory derangement driving immune activation in preeclampsia; in how far the Treg dysfunction is caused by/causes this immune activation in preeclampsia will be the object of future studies.
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Affiliation(s)
- Tina A. Nguyen
- Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California, United States of America
| | - Daniel A. Kahn
- Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California, United States of America
| | - Andrea I. Loewendorf
- Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California, United States of America
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13
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Distinct transcriptome profiles of Gag-specific CD8+ T cells temporally correlated with the protection elicited by SIVΔnef live attenuated vaccine. PLoS One 2017; 12:e0173929. [PMID: 28333940 PMCID: PMC5363825 DOI: 10.1371/journal.pone.0173929] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2016] [Accepted: 02/27/2017] [Indexed: 12/21/2022] Open
Abstract
The live attenuated vaccine (LAV) SIVmac239Δnef (SIVΔnef) confers the best protection among all the vaccine modalities tested in rhesus macaque model of HIV-1 infection. This vaccine has a unique feature of time-dependent protection: macaques are not protected at 3–5 weeks post vaccination (WPV), whereas immune protection emerges between 15 and 20 WPV. Although the exact mechanisms of the time-dependent protection remain incompletely understood, studies suggested that both cellular and humoral immunities contribute to this time-dependent protection. To further elucidate the mechanisms of protection induced by SIVΔnef, we longitudinally compared the global gene expression profiles of SIV Gag-CM9+ CD8+ (Gag-specific CD8+) T cells from peripheral blood of Mamu-A*01+ rhesus macaques at 3 and 20 WPV using rhesus microarray. We found that gene expression profiles of Gag-specific CD8+ T cells at 20 WPV are qualitatively different from those at 3 WPV. At 20 WPV, the most significant transcriptional changes of Gag-specific CD8+ T cells were genes involved in TCR signaling, differentiation and maturation toward central memory cells, with increased expression of CCR7, TCRα, TCRβ, CD28 and decreased expression of CTLA-4, IFN-γ, RANTES, granzyme A and B. Our study suggests that a higher quality of SIV-specific CD8+ T cells elicited by SIVΔnef over time contributes to the maturation of time-dependent protection.
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14
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Moylan DC, Goepfert PA, Kempf MC, Saag MS, Richter HE, Mestecky J, Sabbaj S. Diminished CD103 (αEβ7) Expression on Resident T Cells from the Female Genital Tract of HIV-Positive Women. Pathog Immun 2017; 1:371-387. [PMID: 28164171 PMCID: PMC5288734 DOI: 10.20411/pai.v1i2.166] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Background: Tissue resident memory T cells (TrM) provide an enhanced response against infection at mucosal surfaces, yet their function has not been extensively studied in humans, including the female genital tract (FGT). Methods: Using polychromatic flow cytometry, we studied TrM cells, defined as CD62L-CCR7-CD103+CD69+ CD4+ and CD8+ T cells in mucosa-derived T cells from healthy and HIV-positive women. Results: We demonstrate that TrM are present in the FGT of healthy and HIV-positive women. The expression of the mucosal retention receptor, CD103, from HIV-positive women was reduced compared to healthy women and was lowest in women with CD4 counts < 500 cells/mm3. Furthermore, CD103 expression on mucosa-derived CD8+ T cells correlated with antigen-specific IFN-γ production by mucosal CD4+ T cells and was inversely correlated with T-bet from CD8+CD103+ mucosa-derived T cells. Conclusions: These data suggest that CD4+ T cells, known to be impaired during HIV-1 infection and necessary for the expression of CD103 in murine models, may play a role in the expression of CD103 on resident T cells from the human FGT.
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Affiliation(s)
- David C Moylan
- Departments of Medicine, University of Alabama at Birmingham, Birmingham, AL
| | - Paul A Goepfert
- Departments of Medicine, University of Alabama at Birmingham, Birmingham, AL; Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL
| | - Mirjam-Colette Kempf
- School of Nursing and Department of Health Behavior, University of Alabama at Birmingham, Birmingham, AL
| | - Michael S Saag
- Departments of Medicine, University of Alabama at Birmingham, Birmingham, AL
| | - Holly E Richter
- Obstetrics and Gynecology, University of Alabama at Birmingham, Birmingham, AL
| | - Jiri Mestecky
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL
| | - Steffanie Sabbaj
- Departments of Medicine, University of Alabama at Birmingham, Birmingham, AL
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15
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Common Variable Immunodeficiency patients with a phenotypic profile of immunosenescence present with thrombocytopenia. Sci Rep 2017; 7:39710. [PMID: 28054583 PMCID: PMC5214528 DOI: 10.1038/srep39710] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2016] [Accepted: 11/25/2016] [Indexed: 12/30/2022] Open
Abstract
Common variable immunodeficiency (CVID) is a heterogeneous group of diseases. Our aim was to define sub-groups of CVID patients with similar phenotypes and clinical characteristics. Using eight-color flow cytometry, we analyzed both B- and T-cell phenotypes in a cohort of 88 CVID patients and 48 healthy donors. A hierarchical clustering of probability binning “bins” yielded a separate cluster of 22 CVID patients with an abnormal phenotype. We showed coordinated proportional changes in naïve CD4+ T-cells (decreased), intermediate CD27− CD28+ CD4+ T-cells (increased) and CD21low B-cells (increased) that were stable for over three years. Moreover, the lymphocytes’ immunophenotype in this patient cluster exhibited features of profound immunosenescence and chronic activation. Thrombocytopenia was only found in this cluster (36% of cases, manifested as Immune Thrombocytopenia (ITP) or Evans syndrome). Clinical complications more frequently found in these patients include lung fibrosis (in 59% of cases) and bronchiectasis (55%). The degree of severity of these symptoms corresponded to more deviation from normal levels with respect to CD21low B-cells, naïve CD4+ and CD27− CD28+ over three years. Moreover, th-cells. Next-generation sequencing did not reveal any common genetic background. We delineate a subgroup of CVID patients with activated and immunosenescent immunophenotype of lymphocytes and distinct set of clinical complications without common genetic background.
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16
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HIV-Specific CD8+ T Cell-Mediated Viral Suppression Correlates With the Expression of CD57. J Acquir Immune Defic Syndr 2016; 71:8-16. [PMID: 26761268 DOI: 10.1097/qai.0000000000000837] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Virus-specific CD8(+) T-cell responses are believed to play an important role in the control of HIV-1 infection; however, what constitutes an effective HIV-1 CD8(+) T-cell response remains a topic of debate. The ex vivo viral suppressive capacity was measured of CD8(+) T cells from 44 HIV-1-positive individuals. The phenotypic and cytokine profiles, and also the specificity of the CD8(+) T cells, were correlated with the suppression of HIV-1 replication. We also aimed to determine whether antiretroviral therapy (ART) had any positive effect on the HIV-1 suppressive CD8(+) T cells. METHOD Ex vivo suppression assay was used to evaluate the ability of CD8(+) T cells to suppress HIV-1 replication in autologous CD4(+) T cells. The CD107a, interferon-γ, interleukin-2, tumor necrosis factor-α (TNF-α), and macrophage inflammatory protein-1β (MIP-1β) responses to HIV-1 were evaluated by intracellular staining. The phenotypic profile of CD8(+) T cells was determined by whole blood staining. RESULTS The expression of CD57 on effector CD8(+) T cells correlated with the suppression of HIV-1 replication and to the duration of ART. CD107a and tumor necrosis factor-α expression levels were significantly higher in individuals with ex vivo suppressive activity compared with individuals without suppressive activity. CONCLUSIONS Standard in vitro assays measuring one or several cytokines do not correlate with the functional viral suppressive capacity of CD8(+) T cells from HIV-1-positive individuals. The best correlation of viral suppression was found to be CD57 expression. CD57 expression correlated with the duration of ART, suggesting that ART restores the cytotoxic capacity of CD8(+) T lymphocytes.
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17
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Parodi C, García Bustos MF, Barrio A, Ramos F, González Prieto AG, Mora MC, Baré P, Basombrío MA, de Elizalde de Bracco MM. American tegumentary leishmaniasis: T-cell differentiation profile of cutaneous and mucosal forms-co-infection with Trypanosoma cruzi. Med Microbiol Immunol 2016; 205:353-69. [PMID: 27040974 DOI: 10.1007/s00430-016-0455-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2015] [Accepted: 03/28/2016] [Indexed: 10/22/2022]
Abstract
American tegumentary leishmaniasis displays two main clinical forms: cutaneous (CL) and mucosal (ML). ML is more resistant to treatment and displays a more severe and longer evolution. Since both forms are caused by the same Leishmania species, the immunological response of the host may be an important factor determining the evolution of the disease. Herein, we analyzed the differentiation and memory profile of peripheral CD4(+) and CD8(+) T lymphocytes of patients with CL and ML and their Leishmania-T. cruzi co-infected counterparts. We measured the expression of CD27, CD28, CD45RO, CD127, PD-1 and CD57, together with interferon-γ and perforin. A highly differentiated phenotype was reflected on both T subsets in ML and preferentially on CD8(+) T cells in CL. A positive trend toward a higher T differentiation profile was found in T. cruzi-infected CL and ML patients as compared with Leishmania single infections. Association between CD8(+) T-cell differentiation and illness duration was found within the first year of infection, with progressive increase of highly differentiated markers over time. Follow-up of patients with good response to therapy showed predominance of early differentiated CD8(+) T cells and decrease of highly differentiated cells, while patients with frequent relapses presented the opposite pattern. CD8(+) T cells showed the most striking changes in their phenotype during leishmaniasis. Patients with long-term infections showed the highest differentiated degree implying a relation between T differentiation and parasite persistence. Distinct patterns of CD8(+) T differentiation during follow-up of different clinical outcomes suggest the usefulness of this analysis in the characterization of Leishmania-infected patients.
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Affiliation(s)
- Cecilia Parodi
- Instituto de Patología Experimental-CONICET, Universidad Nacional de Salta, Salta, Argentina. .,Laboratorio de Inmunología, Instituto de Medicina Experimental-CONICET, Academia Nacional de Medicina, Pacheco de Melo 3081, CP1425, Buenos Aires, Argentina.
| | - María F García Bustos
- Instituto de Patología Experimental-CONICET, Universidad Nacional de Salta, Salta, Argentina
| | - Alejandra Barrio
- Cátedra de Microbiología, Facultad de Ciencias de la Salud, Universidad Nacional de Salta, Salta, Argentina
| | - Federico Ramos
- Instituto de Patología Experimental-CONICET, Universidad Nacional de Salta, Salta, Argentina
| | - Ana G González Prieto
- Cátedra de Microbiología, Facultad de Ciencias de la Salud, Universidad Nacional de Salta, Salta, Argentina
| | - María C Mora
- Instituto de Patología Experimental-CONICET, Universidad Nacional de Salta, Salta, Argentina
| | - Patricia Baré
- Laboratorio de Inmunología, Instituto de Medicina Experimental-CONICET, Academia Nacional de Medicina, Pacheco de Melo 3081, CP1425, Buenos Aires, Argentina
| | - Miguel A Basombrío
- Instituto de Patología Experimental-CONICET, Universidad Nacional de Salta, Salta, Argentina
| | - María M de Elizalde de Bracco
- Laboratorio de Inmunología, Instituto de Medicina Experimental-CONICET, Academia Nacional de Medicina, Pacheco de Melo 3081, CP1425, Buenos Aires, Argentina
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18
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Wistuba-Hamprecht K, Haehnel K, Janssen N, Demuth I, Pawelec G. Peripheral blood T-cell signatures from high-resolution immune phenotyping of γδ and αβ T-cells in younger and older subjects in the Berlin Aging Study II. IMMUNITY & AGEING 2015; 12:25. [PMID: 26640505 PMCID: PMC4670504 DOI: 10.1186/s12979-015-0052-x] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/03/2015] [Accepted: 11/24/2015] [Indexed: 01/10/2023]
Abstract
Background Aging and latent infection with Cytomegalovirus (CMV) are thought to be major factors driving the immune system towards immunosenescence, primarily characterized by reduced amounts of naïve T-cells and increased memory T-cells, potentially associated with higher morbidity and mortality. The composition of both major compartments, γδ as well as αβ T-cells, is altered by age and CMV, but detailed knowledge of changes to the γδ subset is currently limited. Results Here, we have surveyed a population of 73 younger (23–35 years) and 144 older (62–85 years) individuals drawn from the Berlin Aging Study II, investigating the distribution of detailed differentiation phenotypes of both γδ and αβ T-cells. Correlation of frequencies and absolute counts of the identified phenotypes with age and the presence of CMV revealed a lower abundance of Vδ2-positive and a higher amount of Vδ1-positive cells. We found higher frequencies of late-differentiated and lower frequencies of early-differentiated cells in the Vδ1+ and Vδ1-Vδ2-, but not in the Vδ2+ populations in elderly CMV-seropositive individuals confirming the association of these Vδ2-negative cells with CMV-immunosurveillance. We identified the highest Vδ1:Vδ2 ratios in the CMV-seropositive elderly. The observed increased CD4:CD8 ratios in the elderly were significantly lower in CMV-seropositive individuals, who also possessed a lower naïve and a larger late-differentiated compartment of CD8+ αβ T-cells, reflecting the consensus in the literature. Conclusions Our findings illustrate in detail the strong influence of CMV on the abundance and differentiation pattern of γδ T-cells as well as αβ T-cells in older and younger people. Mechanisms responsible for the phenotypic alterations in the γδ T-cell compartment, associated both with the presence of CMV and with age require further clarification. Electronic supplementary material The online version of this article (doi:10.1186/s12979-015-0052-x) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Kilian Wistuba-Hamprecht
- Department of Internal Medicine II, University Medical Center, Waldhörnlestr. 22, Tübingen, 72072 Germany ; Department of Dermatology, University Medical Center, Tübingen, Germany
| | - Karin Haehnel
- Department of Internal Medicine II, University Medical Center, Waldhörnlestr. 22, Tübingen, 72072 Germany
| | - Nicole Janssen
- Department of Internal Medicine II, University Medical Center, Waldhörnlestr. 22, Tübingen, 72072 Germany
| | - Ilja Demuth
- Research Group on Geriatrics, Charité - Universitaetsmedizin, Berlin, Germany ; Institute of Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Graham Pawelec
- Department of Internal Medicine II, University Medical Center, Waldhörnlestr. 22, Tübingen, 72072 Germany ; The John van Geest Cancer Research Centre, School of Science and Technology, Nottingham Trent University, Clifton Lane, Nottingham, NG11 8NS UK
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Crauste F, Terry E, Mercier IL, Mafille J, Djebali S, Andrieu T, Mercier B, Kaneko G, Arpin C, Marvel J, Gandrillon O. Predicting pathogen-specific CD8 T cell immune responses from a modeling approach. J Theor Biol 2015; 374:66-82. [PMID: 25846273 DOI: 10.1016/j.jtbi.2015.03.033] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2014] [Revised: 03/04/2015] [Accepted: 03/09/2015] [Indexed: 12/21/2022]
Abstract
The primary CD8 T cell immune response constitutes a major mechanism to fight an infection by intra-cellular pathogens. We aim at assessing whether pathogen-specific dynamical parameters of the CD8 T cell response can be identified, based on measurements of CD8 T cell counts, using a modeling approach. We generated experimental data consisting in CD8 T cell counts kinetics during the response to three different live intra-cellular pathogens: two viruses (influenza, vaccinia) injected intranasally, and one bacteria (Listeria monocytogenes) injected intravenously. All pathogens harbor the same antigen (NP68), but differ in their interaction with the host. In parallel, we developed a mathematical model describing the evolution of CD8 T cell counts and pathogen amount during an immune response. This model is characterized by 9 parameters and includes relevant feedback controls. The model outputs were compared with the three data series and an exhaustive estimation of the parameter values was performed. By focusing on the ability of the model to fit experimental data and to produce a CD8 T cell population mainly composed of memory cells at the end of the response, critical parameters were identified. We show that a small number of parameters (2-4) define the main features of the CD8 T cell immune response and are characteristic of a given pathogen. Among these parameters, two are related to the effector CD8 T cell mediated control of cell and pathogen death. The parameter associated with memory cell death is shown to play no relevant role during the main phases of the CD8 T cell response, yet it becomes essential when looking at the predictions of the model several months after the infection.
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Affiliation(s)
- F Crauste
- Université de Lyon, Université Lyon 1, CNRS UMR 5208, Institut Camille Jordan 43 blvd du 11 novembre 1918, F-69622 Villeurbanne-Cedex, France; Inria Team Dracula, Inria Center Grenoble Rhône-Alpes, France.
| | - E Terry
- Université de Lyon, Université Lyon 1, CNRS UMR 5208, Institut Camille Jordan 43 blvd du 11 novembre 1918, F-69622 Villeurbanne-Cedex, France; Inria Team Dracula, Inria Center Grenoble Rhône-Alpes, France; Université de Lyon, Université Lyon 1, CNRS UMR 5534, Centre de Génétique et de Physiologie Moléculaire et Cellulaire, F-69622 Villeurbanne-Cedex, France.
| | - I Le Mercier
- CIRI, INSERM U1111, CNRS UMR 5308; Université Lyon 1, UMS3444/US8; ENS de Lyon, Université de Lyon, 21 Avenue Tony Garnier, F-69007 Lyon, France.
| | - J Mafille
- CIRI, INSERM U1111, CNRS UMR 5308; Université Lyon 1, UMS3444/US8; ENS de Lyon, Université de Lyon, 21 Avenue Tony Garnier, F-69007 Lyon, France.
| | - S Djebali
- CIRI, INSERM U1111, CNRS UMR 5308; Université Lyon 1, UMS3444/US8; ENS de Lyon, Université de Lyon, 21 Avenue Tony Garnier, F-69007 Lyon, France.
| | - T Andrieu
- CIRI, INSERM U1111, CNRS UMR 5308; Université Lyon 1, UMS3444/US8; ENS de Lyon, Université de Lyon, 21 Avenue Tony Garnier, F-69007 Lyon, France.
| | - B Mercier
- CIRI, INSERM U1111, CNRS UMR 5308; Université Lyon 1, UMS3444/US8; ENS de Lyon, Université de Lyon, 21 Avenue Tony Garnier, F-69007 Lyon, France.
| | - G Kaneko
- Université de Lyon, Université Lyon 1, CNRS UMR 5534, Centre de Génétique et de Physiologie Moléculaire et Cellulaire, F-69622 Villeurbanne-Cedex, France; Université de Lyon, INSA-Lyon, INRIA, Laboratoire d׳InfoRmatique en Image et Systèmes d׳information (LIRIS), CNRS UMR5205, F-69621 Lyon, France.
| | - C Arpin
- CIRI, INSERM U1111, CNRS UMR 5308; Université Lyon 1, UMS3444/US8; ENS de Lyon, Université de Lyon, 21 Avenue Tony Garnier, F-69007 Lyon, France.
| | - J Marvel
- CIRI, INSERM U1111, CNRS UMR 5308; Université Lyon 1, UMS3444/US8; ENS de Lyon, Université de Lyon, 21 Avenue Tony Garnier, F-69007 Lyon, France
| | - O Gandrillon
- Inria Team Dracula, Inria Center Grenoble Rhône-Alpes, France; Université de Lyon, Université Lyon 1, CNRS UMR 5534, Centre de Génétique et de Physiologie Moléculaire et Cellulaire, F-69622 Villeurbanne-Cedex, France.
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Shankar EM, Velu V, Kamarulzaman A, Larsson M. Mechanistic insights on immunosenescence and chronic immune activation in HIV-tuberculosis co-infection. World J Virol 2015; 4:17-24. [PMID: 25674514 PMCID: PMC4308524 DOI: 10.5501/wjv.v4.i1.17] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2014] [Revised: 09/30/2014] [Accepted: 10/27/2014] [Indexed: 02/06/2023] Open
Abstract
Immunosenescence is marked by accelerated degradation of host immune responses leading to the onset of opportunistic infections, where senescent T cells show remarkably higher ontogenic defects as compared to healthy T cells. The mechanistic association between T-cell immunosenescence and human immunodeficiency virus (HIV) disease progression, and functional T-cell responses in HIV-tuberculosis (HIV-TB) co-infection remains to be elaborately discussed. Here, we discussed the association of immunosenescence and chronic immune activation in HIV-TB co-infection and reviewed the role played by mediators of immune deterioration in HIV-TB co-infection necessitating the importance of designing therapeutic strategies against HIV disease progression and pathogenesis.
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Huygens A, Lecomte S, Tackoen M, Olislagers V, Delmarcelle Y, Burny W, Van Rysselberge M, Liesnard C, Larsen M, Appay V, Donner C, Marchant A. Functional Exhaustion Limits CD4+and CD8+T-Cell Responses to Congenital Cytomegalovirus Infection. J Infect Dis 2015; 212:484-94. [DOI: 10.1093/infdis/jiv071] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2014] [Accepted: 01/27/2015] [Indexed: 11/13/2022] Open
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22
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Blom K, Braun M, Pakalniene J, Dailidyte L, Béziat V, Lampen MH, Klingström J, Lagerqvist N, Kjerstadius T, Michaëlsson J, Lindquist L, Ljunggren HG, Sandberg JK, Mickiene A, Gredmark-Russ S. Specificity and dynamics of effector and memory CD8 T cell responses in human tick-borne encephalitis virus infection. PLoS Pathog 2015; 11:e1004622. [PMID: 25611738 PMCID: PMC4303297 DOI: 10.1371/journal.ppat.1004622] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2014] [Accepted: 12/10/2014] [Indexed: 12/23/2022] Open
Abstract
Tick-borne encephalitis virus (TBEV) is transferred to humans by ticks. The virus causes tick-borne encephalitis (TBE) with symptoms such as meningitis and meningoencephalitis. About one third of the patients suffer from long-lasting sequelae after clearance of the infection. Studies of the immune response during TBEV-infection are essential to the understanding of host responses to TBEV-infection and for the development of therapeutics. Here, we studied in detail the primary CD8 T cell response to TBEV in patients with acute TBE. Peripheral blood CD8 T cells mounted a considerable response to TBEV-infection as assessed by Ki67 and CD38 co-expression. These activated cells showed a CD45RA-CCR7-CD127- phenotype at day 7 after hospitalization, phenotypically defining them as effector cells. An immunodominant HLA-A2-restricted TBEV epitope was identified and utilized to study the characteristics and temporal dynamics of the antigen-specific response. The functional profile of TBEV-specific CD8 T cells was dominated by variants of mono-functional cells as the effector response matured. Antigen-specific CD8 T cells predominantly displayed a distinct Eomes+Ki67+T-bet+ effector phenotype at the peak of the response, which transitioned to an Eomes-Ki67-T-bet+ phenotype as the infection resolved and memory was established. These transcription factors thus characterize and discriminate stages of the antigen-specific T cell response during acute TBEV-infection. Altogether, CD8 T cells responded strongly to acute TBEV infection and passed through an effector phase, prior to gradual differentiation into memory cells with distinct transcription factor expression-patterns throughout the different phases. Tick-borne encephalitis virus (TBEV) belongs to the flavivirus family and causes tick-borne encephalitis. This is a severe meningoencephalitic disease with no available treatment. Detailed studies of the immune response during human TBEV infection are essential to understand host responses to TBE and for the development of therapeutics. Herein, we studied the primary T cell-mediated immune response in patients diagnosed with TBEV infection. We show that CD8 T cells mount a vigorous TBEV-specific response within one week of hospitalization. Moreover, TBEV-specific CD8 T cells displayed a distinctive phenotypic and functional profile, paired with a distinct transcription factor expression-pattern during the peak of activation. In summary, this is the first comprehensive study of the CD8 T cell response during acute human TBEV infection, and provides a framework for understanding of CD8 T cell-mediated immunity in this emerging viral disease.
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Affiliation(s)
- Kim Blom
- Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Monika Braun
- Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Jolita Pakalniene
- Department of Infectious Diseases, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Laura Dailidyte
- Department of Infectious Diseases, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Vivien Béziat
- Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
- Human Genetics of Infectious Diseases Laboratory, Imagine Institute—INSERM U1163, Paris, France
| | - Margit H. Lampen
- Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Jonas Klingström
- Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Nina Lagerqvist
- Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Torbjörn Kjerstadius
- Karolinska University Laboratory, Department of Clinical Microbiology, Karolinska University Hospital Solna, Stockholm, Sweden
| | - Jakob Michaëlsson
- Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Lars Lindquist
- Department of Infectious Diseases, Karolinska University Hospital Huddinge, Stockholm, Sweden
- Unit of Infectious Disease, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Hans-Gustaf Ljunggren
- Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Johan K. Sandberg
- Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Aukse Mickiene
- Department of Infectious Diseases, Lithuanian University of Health Sciences, Kaunas, Lithuania
- Unit of Infectious Disease, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Sara Gredmark-Russ
- Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
- Department of Infectious Diseases, Karolinska University Hospital Huddinge, Stockholm, Sweden
- * E-mail:
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Huygens A, Dauby N, Vermijlen D, Marchant A. Immunity to cytomegalovirus in early life. Front Immunol 2014; 5:552. [PMID: 25400639 PMCID: PMC4214201 DOI: 10.3389/fimmu.2014.00552] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Accepted: 10/16/2014] [Indexed: 01/21/2023] Open
Abstract
Cytomegalovirus (CMV) is the most common congenital infection and is the leading non-genetic cause of neurological defects. CMV infection in early life is also associated with intense and prolonged viral excretion, indicating limited control of viral replication. This review summarizes our current understanding of the innate and adaptive immune responses to CMV infection during fetal life and infancy. It illustrates the fact that studies of congenital CMV infection have provided a proof of principle that the human fetus can develop anti-viral innate and adaptive immune responses, indicating that such responses should be inducible by vaccination in early life. The review also emphasizes the fact that our understanding of the mechanisms involved in symptomatic congenital CMV infection remains limited.
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Affiliation(s)
- Ariane Huygens
- Institute for Medical Immunology, Université Libre de Bruxelles , Charleroi , Belgium
| | - Nicolas Dauby
- Institute for Medical Immunology, Université Libre de Bruxelles , Charleroi , Belgium
| | - David Vermijlen
- Faculty of Pharmacy, Université Libre de Bruxelles , Brussels , Belgium
| | - Arnaud Marchant
- Institute for Medical Immunology, Université Libre de Bruxelles , Charleroi , Belgium
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24
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Argüello RJ, Vigliano C, Cabeza-Meckert P, Viotti R, Garelli F, Favaloro LE, Favaloro RR, Laguens R, Laucella SA. Presence of antigen-experienced T cells with low grade of differentiation and proliferative potential in chronic Chagas disease myocarditis. PLoS Negl Trop Dis 2014; 8:e2989. [PMID: 25144227 PMCID: PMC4140664 DOI: 10.1371/journal.pntd.0002989] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2013] [Accepted: 05/19/2014] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND The main consequence of chronic Trypanosoma cruzi infection is the development of myocarditis in approximately 20-30% of infected individuals but not until 10-20 years after the initial infection. We have previously shown that circulating interferon-γ-secreting T cells responsive to Trypanosoma cruzi antigens in chronic Chagas disease patients display a low grade of differentiation and the frequency of these T lymphocytes decreases along with the severity of heart disease. This study thought to explore the expression of inhibitory receptors, transcription factors of type 1 or regulatory T cells, and markers of T cell differentiation, immunosenescence or active cell cycle in cardiac explants from patients with advanced Chagas disease myocarditis. METHODOLOGY/PRINCIPAL FINDINGS The expression of different markers for T and B cells as well as for macrophages was evaluated by immunohistochemistry and immunofluorescence techniques in cardiac explants from patients with advanced chronic Chagas disease submitted to heart transplantation. Most infiltrating cells displayed markers of antigen-experienced T cells (CD3(+), CD4(+), CD8(+), CD45RO(+)) with a low grade of differentiation (CD27(+), CD57(-), CD45RA(-), PD(-)1(-)). A skewed T helper1/T cytotoxic 1 profile was supported by the expression of T-bet; whereas FOXP3(+) cells were scarce and located only in areas of severe myocarditis. In addition, a significant proliferative capacity of CD3(+) T cells, assessed by Ki67 staining, was found. CONCLUSIONS/SIGNIFICANCE The quality of T cell responses and immunoregulatory mechanisms might determine the pattern of the cellular response and the severity of disease in chronic Trypanosoma cruzi infection.
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Affiliation(s)
- Rafael J. Argüello
- Instituto Nacional de Parasitología “Dr. Mario Fatala Chabén”, Buenos Aires, Argentina
| | - Carlos Vigliano
- Departamento de Patología, Hospital Universitario Fundación Favaloro, Buenos Aires, Argentina
| | - Patricia Cabeza-Meckert
- Departamento de Patología, Hospital Universitario Fundación Favaloro, Buenos Aires, Argentina
| | - Rodolfo Viotti
- Servicio de Cardiología, Sección de Chagas, Hospital Interzonal General de Agudos “Eva Perón”, San Martín, Buenos Aires, Argentina
| | - Fernando Garelli
- Laboratorio de Eco-Epidemiología de la enfermedad de Chagas, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Liliana E. Favaloro
- Departamento de Trasplante Intratorácico. Hospital Universitario Fundación Favaloro, Buenos Aires, Argentina
| | - Roberto R. Favaloro
- Departamento de Trasplante Intratorácico. Hospital Universitario Fundación Favaloro, Buenos Aires, Argentina
| | - Rubén Laguens
- Departamento de Patología, Hospital Universitario Fundación Favaloro, Buenos Aires, Argentina
| | - Susana A. Laucella
- Instituto Nacional de Parasitología “Dr. Mario Fatala Chabén”, Buenos Aires, Argentina
- Servicio de Cardiología, Sección de Chagas, Hospital Interzonal General de Agudos “Eva Perón”, San Martín, Buenos Aires, Argentina
- * E-mail:
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Figueiredo S, Charmeteau B, Surenaud M, Salmon D, Launay O, Guillet JG, Hosmalin A, Gahery H. Memory CD8(+) T cells elicited by HIV-1 lipopeptide vaccines display similar phenotypic profiles but differences in term of magnitude and multifunctionality compared with FLU- or EBV-specific memory T cells in humans. Vaccine 2013; 32:492-501. [PMID: 24291199 DOI: 10.1016/j.vaccine.2013.11.052] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2013] [Revised: 10/19/2013] [Accepted: 11/15/2013] [Indexed: 11/16/2022]
Abstract
Differentiation marker, multifunctionality and magnitude analyses of specific-CD8(+) memory T cells are crucial to improve development of HIV vaccines designed to generate cell-mediated immunity. Therefore, we fully characterized the HIV-specific CD8(+) T cell responses induced in volunteers vaccinated with HIV lipopeptide vaccines for phenotypic markers, tetramer staining, cytokine secretion, and cytotoxic activities. The frequency of ex vivo CD8(+) T cells elicited by lipopeptide vaccines is very rare and central-memory phenotype and functions of these cells were been shown to be important in AIDS immunity. So, we expanded them using specific peptides to compare the memory T cell responses induced in volunteers by HIV vaccines with responses to influenza (FLU) or Epstein Barr virus (EBV). By analyzing the differentiation state of IFN-γ-secreting CD8(+) T cells, we found a CCR7(-)CD45RA(-)CD28(+int)/CD28(-) profile (>85%) belonging to a subset of intermediate-differentiated effector T cells for HIV, FLU, and EBV. We then assessed the quality of the response by measuring various T cell functions. The percentage of single IFN-γ T cell producers in response to HIV was 62% of the total of secreting T cells compared with 35% for FLU and EBV, dual and triple (IFN-γ/IL-2/CD107a) T cell producers could also be detected but at lower levels (8% compared with 37%). Finally, HIV-specific T cells secreted IFN-γ and TNF-α, but not the dual combination like FLU- and EBV-specific T cells. Thus, we found that the functional profile and magnitude of expanded HIV-specific CD8(+) T precursors were more limited than those of to FLU- and EBV-specific CD8(+) T cells. These data show that CD8(+) T cells induced by these HIV vaccines have a similar differentiation profile to FLU and EBV CD8(+) T cells, but that the vaccine potency to induce multifunctional T cells needs to be increased in order to improve vaccination strategies.
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Affiliation(s)
- Suzanne Figueiredo
- Inserm U1016, Institut Cochin, Paris, France; CNRS UMR8104, Paris, France; Univ Paris Descartes, Paris, France
| | - Benedicte Charmeteau
- Inserm U1016, Institut Cochin, Paris, France; CNRS UMR8104, Paris, France; Univ Paris Descartes, Paris, France
| | - Mathieu Surenaud
- Inserm U1016, Institut Cochin, Paris, France; CNRS UMR8104, Paris, France; Univ Paris Descartes, Paris, France
| | - Dominique Salmon
- Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Cochin, Paris, France
| | - Odile Launay
- Inserm CIC BT505, CIC de Vaccinologie Cochin Pasteur, Paris, France
| | - Jean-Gérard Guillet
- Inserm U1016, Institut Cochin, Paris, France; CNRS UMR8104, Paris, France; Univ Paris Descartes, Paris, France
| | - Anne Hosmalin
- Inserm U1016, Institut Cochin, Paris, France; CNRS UMR8104, Paris, France; Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Cochin, Paris, France
| | - Hanne Gahery
- Inserm U1016, Institut Cochin, Paris, France; CNRS UMR8104, Paris, France; Univ Paris Descartes, Paris, France; Institut National de Santé et de Recherche Médicale, INSERM U976, Saint-Louis Hospital, Skin Research Center, 75010 Paris, France; Paris Diderot University, Sorbonne Paris Cité, Laboratory of Immunology, Dermatology & Oncology, UMR-S 976, 75010 Paris, France.
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26
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Larbi A, Fulop T. From "truly naïve" to "exhausted senescent" T cells: when markers predict functionality. Cytometry A 2013; 85:25-35. [PMID: 24124072 DOI: 10.1002/cyto.a.22351] [Citation(s) in RCA: 233] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2013] [Revised: 05/27/2013] [Accepted: 07/30/2013] [Indexed: 02/06/2023]
Abstract
The study of T cell biology has been accelerated by substantial progress at the technological level, particularly through the continuing advancement of flow cytometry. The conventional approach of observing T cells as either T helper or T cytotoxic is overly simplistic and does not allow investigators to clearly identify immune mechanisms or alterations in physiological processes that impact on clinical outcomes. The complexity of T cell sub-populations, as we understand them today, combined with the immunological and functional diversity of these subsets represent significant complications for the study of T cell biology. In this article, we review the use of classical markers in delineating T cell sub-populations, from "truly naïve" T cells (recent thymic emigrants with no proliferative history) to "exhausted senescent" T cells (poorly proliferative cells that display severe functional abnormalities) wherein the different phenotypes of these populations reflect their disparate functionalities. In addition, since persistent infections and chronological aging have been shown to be associated with significant alterations in human T cell distribution and function, we also discuss age-associated and cytomegalovirus-driven alterations in the expression of key subset markers.
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Affiliation(s)
- Anis Larbi
- Singapore Immunology Network (SIgN), Biopolis, Agency for Science Technology and Research (A*STAR), Singapore
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27
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Fülöp T, Larbi A, Pawelec G. Human T cell aging and the impact of persistent viral infections. Front Immunol 2013; 4:271. [PMID: 24062739 PMCID: PMC3772506 DOI: 10.3389/fimmu.2013.00271] [Citation(s) in RCA: 230] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2013] [Accepted: 08/27/2013] [Indexed: 12/30/2022] Open
Abstract
Aging is associated with a dysregulation of the immune response, loosely termed “immunosenescence.” Each part of the immune system is influenced to some extent by the aging process. However, adaptive immunity seems more extensively affected and among all participating cells it is the T cells that are most altered. There is a large body of experimental work devoted to the investigation of age-associated differences in T cell phenotypes and functions in young and old individuals, but few longitudinal studies in humans actually delineating changes at the level of the individual. In most studies, the number and proportion of late-differentiated T cells, especially CD8+ T cells, is reported to be higher in the elderly than in the young. Limited longitudinal studies suggest that accumulation of these cells is a dynamic process and does indeed represent an age-associated change. Accumulations of such late-stage cells may contribute to the enhanced systemic pro-inflammatory milieu commonly seen in older people. We do not know exactly what causes these observed changes, but an understanding of the possible causes is now beginning to emerge. A favored hypothesis is that these events are at least partly due to the effects of the maintenance of essential immune surveillance against persistent viral infections, notably Cytomegalovirus (CMV), which may exhaust the immune system over time. It is still a matter of debate as to whether these changes are compensatory and beneficial or pathological and detrimental to the proper functioning of the immune system and whether they impact longevity. Here, we will review present knowledge of T cell changes with aging and their relation to chronic viral and possibly other persistent infections.
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Affiliation(s)
- T Fülöp
- Geriatrics Division, Department of Medicine, Research Center on Aging, University of Sherbrooke , Sherbrooke, QC , Canada
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Abstract
Introduction With 3 – 4 million new infections occurring annually, hepatitis C virus (HCV) is a major global health problem. There is increasing evidence to suggest that HCV will be highly amenable to a vaccine approach, and despite advances in treatment, a vaccine remains the most cost-effective and realistic means to significantly reduce the worldwide mortality and morbidity associated with persistent HCV infection. Areas covered In this review we discuss immune responses to HCV during natural infection, and describe how they may inform vaccine design. We introduce the current candidate vaccines for HCV and compare how these fare against the expected requirements of an effective prophylactic HCV vaccine in relation to the breadth, functionality, magnitude and phenotype of the vaccine-induced immune response. Expert opinion Although the correlates of immune protection against HCV are not completely defined, we now have vaccine technologies capable of inducing HCV-specific adaptive immune responses to an order of magnitude that are associated with protection during natural infection. The challenge next is to i) establish well-characterised cohorts of people at risk of HCV infection for vaccine efficacy testing and ii) to better understand the correlates of protection in natural history studies. If these can be achieved, a vaccine against HCV appears a realistic goal.
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Affiliation(s)
- Leo Swadling
- University of Oxford, NDM and Jenner Institute, Peter Medawar Building, South Parks Road, Oxford, OX1 3SY, UK
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29
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Bateman EAL, Ayers L, Sadler R, Lucas M, Roberts C, Woods A, Packwood K, Burden J, Harrison D, Kaenzig N, Lee M, Chapel HM, Ferry BL. T cell phenotypes in patients with common variable immunodeficiency disorders: associations with clinical phenotypes in comparison with other groups with recurrent infections. Clin Exp Immunol 2013; 170:202-11. [PMID: 23039891 DOI: 10.1111/j.1365-2249.2012.04643.x] [Citation(s) in RCA: 107] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Common variable immunodeficiency disorders (CVID) are a group of heterogeneous conditions that have in common primary failure of B cell function, although numerous T cell abnormalities have been described, including reduced proliferative response and reduced regulatory T cells. This study compared the T cell phenotype of CVID patients subdivided into clinical phenotypes as well as patients with partial antibody deficiencies [immunoglobulin (Ig)G subclass deficiency and selective IgA deficiency], X-linked agammaglobulinaemia (XLA) and healthy and disease controls. Absolute numbers of T cell subpopulations were measured by four-colour flow cytometry: naive T cells, central and effector memory and terminally differentiated (TEM) T cells, using CD45RA and CCR7 expression. Early, intermediate and late differentiation status of T cells was measured by CD27/CD28 expression. Putative follicular T cells, recent thymic emigrants and regulatory T cells were also assessed. Significant reduction in naive CD4 T cells, with reduced total CD4 and recent thymic emigrant numbers, was observed in CVID patients, most pronounced in those with autoimmune cytopenias or polyclonal lymphoproliferation. These findings suggest a lack of replenishment by new thymically derived cells. CD8 naive T cells were reduced in CVID patients, most significantly in the autoimmune cytopenia subgroup. There was a reduction in early differentiated CD4 and CD8 T cells and increased CD8 TEM in the CVID patients, particularly autoimmune cytopenia and polyclonal lymphoproliferation subgroups, suggesting a more activated T cell phenotype, due perhaps to an antigen-driven process. XLA patients had significantly reduced putative follicular T cells, which may depend on B cells for survival, while no significant alterations were observed in the T cells of those with IgG subclass deficiency or selective IgA deficiency.
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Affiliation(s)
- E A L Bateman
- Department of Clinical Laboratory Immunology, Churchill Hospital Clinical Immunology, John Radcliffe Hospital, Oxford, UK
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Blom K, Braun M, Ivarsson MA, Gonzalez VD, Falconer K, Moll M, Ljunggren HG, Michaëlsson J, Sandberg JK. Temporal dynamics of the primary human T cell response to yellow fever virus 17D as it matures from an effector- to a memory-type response. THE JOURNAL OF IMMUNOLOGY 2013; 190:2150-8. [PMID: 23338234 DOI: 10.4049/jimmunol.1202234] [Citation(s) in RCA: 81] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
The live attenuated yellow fever virus (YFV) 17D vaccine provides a good model to study immune responses to an acute viral infection in humans. We studied the temporal dynamics, composition, and character of the primary human T cell response to YFV. The acute YFV-specific effector CD8 T cell response was broad and complex; it was composed of dominant responses that persisted into the memory population, as well as of transient subdominant responses that were not detected at the memory stage. Furthermore, HLA-A2- and HLA-B7-restricted YFV epitope-specific effector cells predominantly displayed a CD45RA(-)CCR7(-)PD-1(+)CD27(high) phenotype, which transitioned into a CD45RA(+)CCR7(-)PD-1(-)CD27(low) memory population phenotype. The functional profile of the YFV-specific CD8 T cell response changed in composition as it matured from an effector- to a memory-type response, and it tended to become less polyfunctional during the course of this transition. Interestingly, activation of CD4 T cells, as well as FOXP3(+) T regulatory cells, in response to YFV vaccination preceded the kinetics of the CD8 T cell response. The present results contribute to our understanding of how immunodominance patterns develop, as well as the phenotypic and functional characteristics of the primary human T cell response to a viral infection as it evolves and matures into memory.
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Affiliation(s)
- Kim Blom
- Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, 141 86 Stockholm, Sweden
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CD4 T cell depletion at the cervix during HIV infection is associated with accumulation of terminally differentiated T cells. J Virol 2011; 85:13333-41. [PMID: 21994461 DOI: 10.1128/jvi.05671-11] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
In blood, the accumulation of terminally differentiated (TD) T cells during HIV infection is associated with CD4 T cell loss and HIV disease progression. Here, we investigated the maintenance and functional characteristics of memory T cells at the cervix. We found that CD4 T cell depletion at the cervix mirrors CD4 depletion in blood. In all women, depletion of CD4 T cells at the cervix was associated with significant reductions in CD45RA- CCR7+ (central memory [CM]) T cells and the accumulation of CD45RA+ CCR7- (TD T cells). We determined whether inflammation in the genital tract was associated with the local differentiation of T cells at the cervix. In uninfected women, genital tract inflammation was associated with the accumulation of CD45RA- CCR7+ CM CD4 T cells and reduced frequencies of CD45RA+ CCR7- TD cells at the cervix. This finding may reflect the fact that, in the absence of HIV infection, TD T cells may be slowly lost in the presence of genital inflammation, while CD45RA- CCR7+ CM T cells are recruited to replenish the diminishing CD4 T cell pool. Following global stimulation with phorbol myristate acetate (PMA)-ionomycin, we noted a significant interleukin 2 (IL-2) deficit in both cervical and blood CD4 T cells from HIV-infected women compared to uninfected women, while gamma interferon (IFN-γ) production was similar, irrespective of HIV status. Few HIV-infected women had detectable IFN-γ and IL-2 HIV-specific T cell responses at the cervix, and these responses were significantly lower in magnitude than the corresponding responses in blood. These data suggest that CD4 depletion was associated with the accumulation of terminally differentiated T cell phenotypes at the cervical mucosa defective in their ability to produce IL-2. CD4 depletion and compromised immunity at the cervix may be accompanied by progressive decline of central memory-like T cells and development of T cells toward terminally differentiated phenotypes.
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Terry E, Marvel J, Arpin C, Gandrillon O, Crauste F. Mathematical model of the primary CD8 T cell immune response: stability analysis of a nonlinear age-structured system. J Math Biol 2011; 65:263-91. [PMID: 21842166 DOI: 10.1007/s00285-011-0459-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2011] [Revised: 07/25/2011] [Indexed: 01/07/2023]
Abstract
The primary CD8 T cell immune response, due to a first encounter with a pathogen, happens in two phases: an expansion phase, with a fast increase of T cell count, followed by a contraction phase. This contraction phase is followed by the generation of memory cells. These latter are specific of the antigen and will allow a faster and stronger response when encountering the antigen for the second time. We propose a nonlinear mathematical model describing the T CD8 immune response to a primary infection, based on three nonlinear ordinary differential equations and one nonlinear age-structured partial differential equation, describing the evolution of CD8 T cell count and pathogen amount. We discuss in particular the roles and relevance of feedback controls that regulate the response. First we reduce our system to a system with a nonlinear differential equation with a distributed delay. We study the existence of two steady states, and we analyze the asymptotic stability of these steady states. Second we study the system with a discrete delay, and analyze global asymptotic stability of steady states. Finally, we show some simulations that we can obtain from the model and confront them to experimental data.
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Affiliation(s)
- Emmanuelle Terry
- Université de Lyon, Université Lyon 1, CNRS UMR 5208, Institut Camille Jordan, 43 blvd du 11 novembre 1918, 69622, Villeurbanne-Cedex, France.
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Strioga M, Pasukoniene V, Characiejus D. CD8+ CD28- and CD8+ CD57+ T cells and their role in health and disease. Immunology 2011; 134:17-32. [PMID: 21711350 DOI: 10.1111/j.1365-2567.2011.03470.x] [Citation(s) in RCA: 361] [Impact Index Per Article: 25.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Chronic antigenic stimulation leads to gradual accumulation of late-differentiated, antigen-specific, oligoclonal T cells, particularly within the CD8(+) T-cell compartment. They are characterized by critically shortened telomeres, loss of CD28 and/or gain of CD57 expression and are defined as either CD8(+) CD28(-) or CD8(+) CD57(+) T lymphocytes. There is growing evidence that the CD8(+) CD28(-) (CD8(+) CD57(+)) T-cell population plays a significant role in various diseases or conditions, associated with chronic immune activation such as cancer, chronic intracellular infections, chronic alcoholism, some chronic pulmonary diseases, autoimmune diseases, allogeneic transplantation, as well as has a great influence on age-related changes in the immune system status. CD8(+) CD28(-) (CD8(+) CD57(+)) T-cell population is heterogeneous and composed of various functionally competing (cytotoxic and immunosuppressive) subsets thus the overall effect of CD8(+) CD28(-) (CD8(+) CD57(+)) T-cell-mediated immunity depends on the predominance of a particular subset. Many articles claim that CD8(+) CD28(-) (CD8(+) CD57(+)) T cells have lost their proliferative capacity during process of replicative senescence triggered by repeated antigenic stimulation. However recent data indicate that CD8(+) CD28(-) (CD8(+) CD57(+)) T cells can transiently up-regulate telomerase activity and proliferate under certain stimulation conditions. Similarly, conflicting data is provided regarding CD8(+) CD28(-) (CD8(+) CD57(+)) T-cell sensitivity to apoptosis, finally leading to the conclusion that this T-cell population is also heterogeneous in terms of its apoptotic potential. This review provides a comprehensive approach to the CD8(+) CD28(-) (CD8(+) CD57(+)) T-cell population: we describe in detail its origins, molecular and functional characteristics, subsets, role in various diseases or conditions, associated with persistent antigenic stimulation.
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Affiliation(s)
- Marius Strioga
- Laboratory of Immunology, Institute of Oncology, Vilnius University, Vilnius Faculty of Medicine, Vilnius University, Vilnius, Lithuania.
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Carotenuto P, Artsen A, Osterhaus AD, Pontesilli O. Reciprocal changes of naïve and effector/memory CD8+ T lymphocytes in chronic hepatitis B virus infection. Viral Immunol 2011; 24:27-33. [PMID: 21319976 DOI: 10.1089/vim.2010.0067] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Persistent viruses, such as cytomegalovirus or human immunodeficiency virus, cause major perturbations of CD8+ T-lymphocyte subpopulations. To test whether chronic infection with hepatitis B virus (HBV) could also be responsible for such modifications, we analyzed the expression of CD27, CD28, CCR7, and perforin in blood CD8+ T lymphocytes. In comparison to healthy subjects and patients recovering from acute hepatitis B, chronic hepatitis B patients showed higher percentages of naïve CD8+ T lymphocytes (CD45RA+CD27+CD28+), and lower percentages of intermediately-differentiated CD27+CD28⁻CD8+ T cells. The late differentiated CD45RA+CD27⁻CD28⁻ subset was also present in a large percentage in some patients, but no statistically significant difference with healthy controls was observed. Removal from the circulation of intermediately-differentiated CD8+ T lymphocytes may occur during chronic HBV infection, favoring the recruitment of naïve cells. This may result in impairment of the generation of functionally-competent memory cells, and an inability to achieve control of HBV replication.
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Baitsch L, Baumgaertner P, Devêvre E, Raghav SK, Legat A, Barba L, Wieckowski S, Bouzourene H, Deplancke B, Romero P, Rufer N, Speiser DE. Exhaustion of tumor-specific CD8⁺ T cells in metastases from melanoma patients. J Clin Invest 2011; 121:2350-60. [PMID: 21555851 DOI: 10.1172/jci46102] [Citation(s) in RCA: 657] [Impact Index Per Article: 46.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2010] [Accepted: 03/16/2011] [Indexed: 12/14/2022] Open
Abstract
In chronic viral infections, CD8⁺ T cells become functionally deficient and display multiple molecular alterations. In contrast, only little is known of self- and tumor-specific CD8⁺ T cells from mice and humans. Here we determined molecular profiles of tumor-specific CD8⁺ T cells from melanoma patients. In peripheral blood from patients vaccinated with CpG and the melanoma antigen Melan-A/MART-1 peptide, we found functional effector T cell populations, with only small but nevertheless significant differences in T cells specific for persistent herpesviruses (EBV and CMV). In contrast, Melan-A/MART-1-specific T cells isolated from metastases from patients with melanoma expressed a large variety of genes associated with T cell exhaustion. The identified exhaustion profile revealed extended molecular alterations. Our data demonstrate a remarkable coexistence of effector cells in circulation and exhausted cells in the tumor environment. Functional T cell impairment is mediated by inhibitory receptors and further molecular pathways, which represent potential targets for cancer therapy.
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Affiliation(s)
- Lukas Baitsch
- Clinical Tumor Immune-Biology Unit, Ludwig Institute for Cancer Research, Lausanne, Switzerland
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Yamamoto T, Price DA, Casazza JP, Ferrari G, Nason M, Chattopadhyay PK, Roederer M, Gostick E, Katsikis PD, Douek DC, Haubrich R, Petrovas C, Koup RA. Surface expression patterns of negative regulatory molecules identify determinants of virus-specific CD8+ T-cell exhaustion in HIV infection. Blood 2011; 117:4805-15. [PMID: 21398582 PMCID: PMC3100691 DOI: 10.1182/blood-2010-11-317297] [Citation(s) in RCA: 165] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2010] [Accepted: 03/06/2011] [Indexed: 01/07/2023] Open
Abstract
A highly complex network of coinhibitory and costimulatory receptors regulates the outcome of virus-specific CD8(+) T-cell responses. Here, we report on the expression patterns of multiple inhibitory receptors on HIV-specific, cytomegalovirus-specific, and bulk CD8(+) T-cell memory populations. In contrast to cytomegalovirus-specific CD8(+) T cells, the majority of HIV-specific CD8(+) T cells exhibited an immature phenotype and expressed Programmed Death-1, CD160 and 2B4 but not lymphocyte activation gene-3. Notably, before antiretroviral therapy, simultaneous expression of these negative regulators correlated strongly with both HIV load and impaired cytokine production. Suppression of HIV replication by antiretroviral therapy was associated with reduced surface expression of inhibitory molecules on HIV-specific CD8(+) T cells. Furthermore, in vitro manipulation of Programmed Death-1 and 2B4 inhibitory pathways increased the proliferative capacity of HIV-specific CD8(+) T cells. Thus, multiple coinhibitory receptors can affect the development of HIV-specific CD8(+) T-cell responses and, by extension, represent potential targets for new immune-based interventions in HIV-infected persons.
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Salaun B, Yamamoto T, Badran B, Tsunetsugu-Yokota Y, Roux A, Baitsch L, Rouas R, Fayyad-Kazan H, Baumgaertner P, Devevre E, Ramesh A, Braun M, Speiser D, Autran B, Martiat P, Appay V, Romero P. Differentiation associated regulation of microRNA expression in vivo in human CD8+ T cell subsets. J Transl Med 2011; 9:44. [PMID: 21507256 PMCID: PMC3098162 DOI: 10.1186/1479-5876-9-44] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2011] [Accepted: 04/20/2011] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND The differentiation of CD8+ T lymphocytes following priming of naïve cells is central in the establishment of the adaptive immune response. Yet, the molecular events underlying this process are not fully understood. MicroRNAs have been recently shown to play a key role in the regulation of haematopoiesis in mouse, but their implication in peripheral lymphocyte differentiation in humans remains largely unknown. METHODS In order to explore the potential implication of microRNAs in CD8+ T cell differentiation in humans, microRNA expression profiles were analysed using microarrays and quantitative PCR in several human CD8+ T cell subsets defining the major steps of the T cell differentiation pathway. RESULTS We found expression of a limited set of microRNAs, including the miR-17~92 cluster. Moreover, we reveal the existence of differentiation-associated regulation of specific microRNAs. When compared to naive cells, miR-21 and miR-155 were indeed found upregulated upon differentiation to effector cells, while expression of the miR-17~92 cluster tended to concomitantly decrease. CONCLUSIONS This study establishes for the first time in a large panel of individuals the existence of differentiation associated regulation of microRNA expression in human CD8+ T lymphocytes in vivo, which is likely to impact on specific cellular functions.
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Affiliation(s)
- Bruno Salaun
- Division of Clinical Onco-Immunology, Ludwig Center for Cancer Research of the University of Lausanne, Switzerland
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Exley AR, Buckenham S, Hodges E, Hallam R, Byrd P, Last J, Trinder C, Harris S, Screaton N, Williams AP, Taylor AMR, Shneerson JM. Premature ageing of the immune system underlies immunodeficiency in ataxia telangiectasia. Clin Immunol 2011; 140:26-36. [PMID: 21459046 DOI: 10.1016/j.clim.2011.03.007] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2010] [Revised: 02/18/2011] [Accepted: 03/03/2011] [Indexed: 10/18/2022]
Abstract
ATM kinase modulates pathways implicated in premature ageing and ATM genotype predicts survival, yet immunodeficiency in ataxia telangiectasia is regarded as mild and unrelated to age. We address this paradox in a molecularly characterised sequential adult cohort with classical and mild variant ataxia telangiectasia. Immunodeficiency has the characteristics of premature ageing across multiple cellular and molecular immune parameters. This immune ageing occurs without previous CMV infection. Age predicts immunodeficiency in genetically homogeneous ataxia telangiectasia, and in comparison with controls, calendar age is exceeded by immunological age defined by thymic naïve CD4+ T cell levels. Applying ataxia telangiectasia as a model of immune ageing, pneumococcal vaccine responses, characteristically deficient in physiological ageing, are predicted by thymic naïve CD4+ T cell levels. These data suggest inherited defects of DNA repair may provide valuable insight into physiological ageing. Thymic naïve CD4+ T cells may provide a biomarker for vaccine responsiveness in elderly cohorts.
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Affiliation(s)
- Andrew Robert Exley
- Immunology Laboratory, Department of Pathology, Papworth Hospital NHS Foundation Trust, Cambridge University Health Partners, Cambridge CB23 3RE, UK.
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Insights into human CD8(+) T-cell memory using the yellow fever and smallpox vaccines. Immunol Cell Biol 2011; 89:340-5. [PMID: 21301482 DOI: 10.1038/icb.2010.155] [Citation(s) in RCA: 80] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Live virus vaccines provide a unique opportunity to study human CD8(+) T-cell memory in the context of a controlled, primary acute viral infection. Yellow fever virus-17D and Dryvax are two such live-virus vaccines that are highly efficacious, used worldwide and provide long-term immunity against yellow fever and smallpox respectively. In this review, we describe the properties of virus-specific memory CD8(+) T cells generated in smallpox and yellow fever vaccinees. We address fundamental questions regarding magnitude, functional quality and longevity of the CD8(+) T-cell response, which are otherwise challenging to address in humans. These findings provide insights into the attributes of the human immune system as well as provide a benchmark for the optimal quality of a CD8(+) T-cell response that can be used to evaluate novel candidate vaccines.
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López M, Soriano V, Peris-Pertusa A, Rallón N, Restrepo C, Benito JM. Elite controllers display higher activation on central memory CD8 T cells than HIV patients successfully on HAART. AIDS Res Hum Retroviruses 2011; 27:157-65. [PMID: 20964478 DOI: 10.1089/aid.2010.0107] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
T cell activation plays an important role in driving CD4 depletion during the course of HIV infection. There is scarce information about activation of different T cell subsets in HIV(+) individuals experiencing distinct disease progression. The activation of different CD4(+) and CD8(+) T cell subsets and its contribution to total T cell activation were examined measuring CD38 expression by flow cytometry in 120 HIV-infected individuals and 9 uninfected healthy controls. HIV-infected patients were divided into four groups: 11 elite controllers (EC), 14 viremic controllers (VC), 61 antiretroviral-naive typical progressors (TP), and 34 progressors with viral suppression (VS) under antiretroviral therapy. EC displayed significantly greater activation levels than VS, with a higher contribution of central memory subsets to the activation of total CD8 T cells (p = 0.002). The activation of central memory CD8(+) T cells significantly correlated with viral load in TP regardless of CD4 counts. In contrast with VS, proviral load was undetectable in all EC. Compared to VS, EC display abnormal and higher activation levels of different CD8(+) T cell subsets. Factors other than the size of the viral reservoir should explain the high level of activation of central memory CD8(+) T cells characteristically seen in HIV(+) individuals with spontaneous control of viral replication.
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Affiliation(s)
- Mariola López
- Infectious Diseases, Hospital Carlos III, Madrid, Spain
| | | | | | - Norma Rallón
- Infectious Diseases, Hospital Carlos III, Madrid, Spain
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Clonal expansion and TCR-independent differentiation shape the HIV-specific CD8+ effector-memory T-cell repertoire in vivo. Blood 2010; 116:396-405. [PMID: 20424187 DOI: 10.1182/blood-2009-11-254136] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Flexibility of the HIV-specific T-cell receptor repertoire is a hallmark of HIV-1 infection. Altered differentiation of HIV-specific CD45RO(+)/CCR7(-) (TemRO) CD8(+) effector-memory T cells into CD45RA(+)/CCR7(-) (TemRA) CD8(+) effector-memory T cells as well as increased expression of the senescence marker CD57 has been frequently observed HIV-1 infection, but the structural relationship between clonal expansion and T-cell differentiation has not been defined. In this study, we demonstrate that HIV-specific clonotypes have differing degrees of TemRA differentiation but always maintain a significant proportion of TemRO-phenotype cells. These data indicate that structural constraints of the TCR/peptide major histocompatibility complex interaction play a central role in the TemRA differentiation of HIV-specific CD8(+) T cells in chronic HIV-1 infection. Clonotypes with a predominantly TemRA phenotype had a substantial fraction of cells without expression of CD57; and in contrast to the high clonotypic variability of TemRA differentiation, expression of CD57 was highly correlated among T-cell clonotypes within epitope-specific responses, indicating TCR-independent expression of CD57 in vivo. Our data highlight the importance of the structural composition of the TCR repertoire for the effector-memory differentiation of the immune response in chronic viral infections and suggest that TCR-dependent and -independent homeostasis shapes the pathogen-specific effector-memory repertoire in vivo.
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Akondy RS, Monson ND, Miller JD, Edupuganti S, Teuwen D, Wu H, Quyyumi F, Garg S, Altman JD, Del Rio C, Keyserling HL, Ploss A, Rice CM, Orenstein WA, Mulligan MJ, Ahmed R. The yellow fever virus vaccine induces a broad and polyfunctional human memory CD8+ T cell response. THE JOURNAL OF IMMUNOLOGY 2010; 183:7919-30. [PMID: 19933869 DOI: 10.4049/jimmunol.0803903] [Citation(s) in RCA: 264] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
The live yellow fever vaccine (YF-17D) offers a unique opportunity to study memory CD8(+) T cell differentiation in humans following an acute viral infection. We have performed a comprehensive analysis of the virus-specific CD8(+) T cell response using overlapping peptides spanning the entire viral genome. Our results showed that the YF-17D vaccine induces a broad CD8(+) T cell response targeting several epitopes within each viral protein. We identified a dominant HLA-A2-restricted epitope in the NS4B protein and used tetramers specific for this epitope to track the CD8(+) T cell response over a 2 year period. This longitudinal analysis showed the following. 1) Memory CD8(+) T cells appear to pass through an effector phase and then gradually down-regulate expression of activation markers and effector molecules. 2) This effector phase was characterized by down-regulation of CD127, Bcl-2, CCR7, and CD45RA and was followed by a substantial contraction resulting in a pool of memory T cells that re-expressed CD127, Bcl-2, and CD45RA. 3) These memory cells were polyfunctional in terms of degranulation and production of the cytokines IFN-gamma, TNF-alpha, IL-2, and MIP-1beta. 4) The YF-17D-specific memory CD8(+) T cells had a phenotype (CCR7(-)CD45RA(+)) that is typically associated with terminally differentiated cells with limited proliferative capacity (T(EMRA)). However, these cells exhibited robust proliferative potential showing that expression of CD45RA may not always associate with terminal differentiation and, in fact, may be an indicator of highly functional memory CD8(+) T cells generated after acute viral infections.
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Affiliation(s)
- Rama S Akondy
- Emory Vaccine Center and the Hope Clinic, Emory University School of Medicine, Atlanta, GA 30022, USA
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Downey JS, Imami N. T-cell dysfunction in HIV-1 infection: targeting the inhibitors. ACTA ACUST UNITED AC 2010. [DOI: 10.2217/hiv.09.51] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Since AIDS emerged almost three decades ago, there have been considerable advances in the field of antiretroviral chemotherapy for those chronically infected with HIV-1. However, this therapy is noncurative and as our understanding of HIV-1 immunopathogenesis increases, it is becoming apparent that further therapeutic interventions are required to reverse the devastating effects of HIV-1 infection worldwide. While viral clearance remains the principle goal of HIV-1 treatment, this article describes immunotherapeutic options that target the immunological effects of the virus, to reduce its presence in the body and counteract viral-induced T-cell dysfunction and inhibition. Such approaches may augment existing antiretroviral therapy to overturn virus-induced T-cell anergy in the infected host, improving levels of immune control that reduce viremia and decrease the rate of transmission.
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Affiliation(s)
- Jocelyn S Downey
- Department of Immunology, Imperial College London, Chelsea & Westminster Hospital, 369 Fulham Road, London, SW10 9NH, UK
| | - Nesrina Imami
- Department of Immunology, Imperial College London, Chelsea & Westminster Hospital, 369 Fulham Road, London, SW10 9NH, UK
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Li Y, Liu S, Hernandez J, Vence L, Hwu P, Radvanyi L. MART-1-specific melanoma tumor-infiltrating lymphocytes maintaining CD28 expression have improved survival and expansion capability following antigenic restimulation in vitro. THE JOURNAL OF IMMUNOLOGY 2009; 184:452-65. [PMID: 19949105 DOI: 10.4049/jimmunol.0901101] [Citation(s) in RCA: 75] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
We determined how CD8(+) melanoma tumor-infiltrating lymphocytes (TILs) isolated from two distinct phases of expansion in preparation for adoptive T cell therapy respond to melanoma Ag restimulation. We found that TILs isolated after the rapid expansion protocol (REP) phase, used to generate the final patient TIL infusion product, were hyporesponsive to restimulation with MART-1 peptide-pulsed dendritic cells, with many CD8(+) T cells undergoing apoptosis. Telomere length was shorter post-REP, but of sufficient length to support further cell division. Phenotypic analysis revealed that cell-surface CD28 expression was significantly reduced in post-REP TILs, whereas CD27 levels remained unchanged. Tracking post-REP TIL proliferation by CFSE dilution, as well as sorting for CD8(+)CD28(+) and CD8(+)CD28(-) post-REP subsets, revealed that the few CD28(+) TILs remaining post-REP had superior survival capacity and proliferated after restimulation with MART-1 peptide. An analysis of different supportive cytokine mixtures during the REP found that a combination of IL-15 and IL-21 facilitated comparable expansion of CD8(+) TILs as IL-2, but prevented the loss of CD28 expression with improved responsiveness to antigenic restimulation post-REP. These results suggest that current expansion protocols using IL-2 for melanoma adoptive T cell therapy yields largely CD8(+) T cells unable to persist and divide in vivo following Ag contact. The few CD8(+)CD28(+) T cells that remain may be the only CD8(+) TILs that ultimately survive to repopulate the host and mediate long-term tumor control. A REP protocol using IL-15 and IL-21 may greatly increase the number of CD28(+) TILs capable of long-term persistence.
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Affiliation(s)
- Yufeng Li
- Department of Melanoma Medical Oncology, Graduate School of Biomedical Sciences, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA
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Adoptively transferred effector cells derived from naive rather than central memory CD8+ T cells mediate superior antitumor immunity. Proc Natl Acad Sci U S A 2009; 106:17469-74. [PMID: 19805141 DOI: 10.1073/pnas.0907448106] [Citation(s) in RCA: 311] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
Effector cells derived from central memory CD8(+) T cells were reported to engraft and survive better than those derived from effector memory populations, suggesting that they are superior for use in adoptive immunotherapy studies. However, previous studies did not evaluate the relative efficacy of effector cells derived from naïve T cells. We sought to investigate the efficacy of tumor-specific effector cells derived from naïve or central memory T-cell subsets using transgenic or retrovirally transduced T cells engineered to express a tumor-specific T-cell receptor. We found that naïve, rather than central memory T cells, gave rise to an effector population that mediated superior antitumor immunity upon adoptive transfer. Effector cells developed from naïve T cells lost the expression of CD62L more rapidly than those derived from central memory T cells, but did not acquire the expression of KLRG-1, a marker for terminal differentiation and replicative senescence. Consistent with this KLRG-1(-) phenotype, naïve-derived cells were capable of a greater proliferative burst and had enhanced cytokine production after adoptive transfer. These results indicate that insertion of genes that confer antitumor specificity into naïve rather than central memory CD8(+) T cells may allow superior efficacy upon adoptive transfer.
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Karrer U, Mekker A, Wanke K, Tchang V, Haeberli L. Cytomegalovirus and immune senescence: culprit or innocent bystander? Exp Gerontol 2009; 44:689-94. [PMID: 19766181 DOI: 10.1016/j.exger.2009.09.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2009] [Revised: 09/04/2009] [Accepted: 09/14/2009] [Indexed: 10/20/2022]
Abstract
Immune senescence may be defined as the age-related reduction and dysregulation of immune function, and has been associated with increased incidence and severity of infectious diseases and with poor efficacy of prophylactic vaccines in the elderly. Several studies have demonstrated that persistent infections with Herpes viruses in general and Cytomegalovirus (CMV) in particular have a profound influence on subset distribution, phenotype and potentially also on the function of T cells in ageing individuals. The association of CMV-seropositivity and accumulation of CMV-specific CD8+ T cells with decreased survival in longitudinal studies of very elderly has fostered the hypothesis that CMV-infection may be an important causative factor for the development of immune senescence. Here, we have critically summarized the current body of evidence supporting this hypothesis, highlight some controversial issues about its relevance and mechanisms and propose areas of future research to demonstrate unequivocally whether and how persistent infections might compromise the ageing immune system.
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Affiliation(s)
- Urs Karrer
- Division of Infectious Diseases and Hospital Epidemiology, University Hospital of Zurich, Ramistrasse 100, CH-8091 Zurich, Switzerland.
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Antiretroviral therapy restores diversity in the T-cell receptor Vbeta repertoire of CD4 T-cell subpopulations among human immunodeficiency virus type 1-infected children and adolescents. CLINICAL AND VACCINE IMMUNOLOGY : CVI 2009; 16:1293-301. [PMID: 19605599 DOI: 10.1128/cvi.00074-09] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Human immunodeficiency virus (HIV) type 1 infection perturbs the T-cell receptor (TCR) Vbeta repertoire. The TCR CDR3 length diversity of individual Vbeta families was examined within CD45RA and CD45RO CD4 T cells to assess the impact of the virus on clonality throughout CD4 T-cell activation and differentiation. A cross-sectional and longitudinal cohort study of 13 HIV-infected and 8 age-matched healthy children and adolescents examined the Vbeta CDR3 length profiles within CD4 T-cell subsets by the use of spectratyping. HIV-infected subjects demonstrated higher numbers of perturbations in CD4 CD45RA T cells (5.8 +/- 4.9 Vbeta families) than healthy individuals (1.6 +/- 1.8 Vbeta families) (P = 0.04). Surprisingly, CD4 CD45RO central memory T cells from infected subjects showed no increased perturbations compared to the perturbations for the same cells from healthy subjects (2.9 +/- 3.1 and 1.1 +/- 1.8 Vbeta families, respectively; P = 0.11). CD4 CD45RA TCR perturbations were higher among infected subjects with >25% CD4 cells than healthy subjects (mean number of perturbed Vbeta families, 6.6 +/- 5.4; P = 0.04). No correlations between perturbations in CD4 subsets and pretherapy age or viral load were evident. In contrast to CD8 T cells, HIV induces TCR disruptions within CD45RA but not CD45RO CD4 T cells. Therapy-induced viral suppression resulted in increases in thymic output and the normalization of the diversity of TCR within CD45RA CD4 T cells after 2 months of treatment. Perturbations occur prior to CD4 T-cell attrition and normalize with effective antiretroviral therapy. The impact of HIV on the diversity of TCR within naïve, central memory, and effector memory CD4 T cells is distinctly different from that in CD8 T cells.
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Brestrich G, Zwinger S, Fischer A, Schmück M, Röhmhild A, Hammer MH, Kurtz A, Uharek L, Knosalla C, Lehmkuhl H, Volk HD, Reinke P. Adoptive T-cell therapy of a lung transplanted patient with severe CMV disease and resistance to antiviral therapy. Am J Transplant 2009; 9:1679-84. [PMID: 19459791 DOI: 10.1111/j.1600-6143.2009.02672.x] [Citation(s) in RCA: 81] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Infections with cytomegalovirus (CMV) can induce severe complications after transplantation, particularly in patients resistant to virostatic therapy. Adoptive transfer of CMV-specific T-cell lines has demonstrated promising results in patients after hematopoietic stem cell transplantation. However, the generation of specific T-cell lines ex vivo and their function in vivo is complicated in solid organ transplant (SOT) recipients. Here, we present the successful adoptive transfer of autologous CMV-specific T cells to a lung transplant recipient with ganciclovir-resistant CMV-pneumonia requiring mechanical ventilation. Infused T cells rapidly expanded in vivo and efficiently inhibited viral replication as confirmed by extensive longitudinal immunological monitoring. After full recovery, the patient was released from the clinic. After 4 weeks, the infection reappeared and persisted at a low level even after a second T-cell infusion. Our experimental data indicate that this could be the consequence of the late differentiated phenotype of the infused T cells and therefore their insufficient longevity in vivo. In summary, our report signifies the high therapeutic potential of adoptive immunotherapy in the treatment of SOT recipients when all other measures show no effect. Further studies have to elucidate the most potent strategies to generate antigen-specific T cells with high functional capacity and robust long-term persistence.
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Affiliation(s)
- G Brestrich
- Department of Nephrology and Internal Intensive Care, Universitätsmedizin, Berlin, Germany.
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Puan KJ, Low JSH, Tan TWK, Wee JTS, Tan EH, Fong KW, Chua ET, Jin C, Giner JL, Morita CT, Goh CHK, Hui KM. Phenotypic and functional alterations of Vgamma2Vdelta2 T cell subsets in patients with active nasopharyngeal carcinoma. Cancer Immunol Immunother 2009; 58:1095-107. [PMID: 19043708 PMCID: PMC2695875 DOI: 10.1007/s00262-008-0629-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2008] [Accepted: 11/12/2008] [Indexed: 11/27/2022]
Abstract
INTRODUCTION Human Vgamma2Vdelta2 T cells play important role in immunity to infection and cancer by monitoring self and foreign isoprenoid metabolites with their gammadelta T cell antigen receptors. Like CD4 and CD8 alphabeta T cells, adult peripheral Vgamma2Vdelta2 T cells represent a pool of heterogeneous cells with distinct functional capabilities. PURPOSE The aim of this study was to characterize the phenotypes and functions of various Vgamma2Vdelta2 T cell subsets in patients with nasopharyngeal carcinoma (NPC). We sought to develop a better understanding of the role of these cells during the course of disease and to facilitate the development of immunotherapeutic strategies against NPC. RESULTS Although similar total percentages of peripheral blood Vgamma2Vdelta2 T cells were found in both NPC patients and normal donors, Vgamma2Vdelta2 T cells from NPC patients showed decreased cytotoxicity against tumor cells whereas Vgamma2Vdelta2 T cells from normal donors showed potent cytotoxicity. To investigate further, we compared the phenotypic characteristics of Vgamma2Vdelta2 T cells from 96 patients with NPC and 54 healthy controls. The fraction of late effector memory Vgamma2Vdelta2 T cells (T(EM RA)) was significantly increased in NPC patients with corresponding decreases in the fraction of early memory Vgamma2Vdelta2 T cells (T(CM)) compared with those in healthy controls. Moreover, T(EM RA) and T(CM) Vgamma2Vdelta2 cells from NPC patients produced significantly less IFN-gamma and TNF-alpha, potentially contributing to their impaired cytotoxicity. Radiotherapy or concurrent chemo-radiotherapy further increased the T(EM RA) Vgamma2Vdelta2 T cell population but did not correct the impaired production of IFN-gamma and TNF-alpha observed for T(EM RA) Vgamma2Vdelta2 T cells. CONCLUSION We have identified distinct alterations in the Vgamma2Vdelta2 T cell subsets of patients with NPC. Moreover, the overall cellular effector function of gammadelta T cells is compromised in these patients. Our data suggest that the contribution of Vgamma2Vdelta2 T cells to control NPC may depend on the activation state and differentiation of these cells.
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Affiliation(s)
- Kia Joo Puan
- Bek Chai Heah Laboratory of Cancer Genomics, Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, 11 Hospital Drive, Singapore 169610, Singapore.
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Parodi C, Padilla AM, Basombrío MA. Protective immunity against Trypanosoma cruzi. Mem Inst Oswaldo Cruz 2009; 104 Suppl 1:288-94. [DOI: 10.1590/s0074-02762009000900038] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2009] [Accepted: 05/08/2009] [Indexed: 02/05/2023] Open
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