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1
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White E, Appay V. [Rejuvenation of CD8 + T cell responses in long-term treated people with HIV]. Med Sci (Paris) 2025; 41:229-232. [PMID: 40117545 DOI: 10.1051/medsci/2025031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/23/2025] Open
Affiliation(s)
- Eoghann White
- Université de Bordeaux, CNRS UMR 5164, Inserm ERL 1303, ImmunoConcEpT, Bordeaux, France
| | - Victor Appay
- Université de Bordeaux, CNRS UMR 5164, Inserm ERL 1303, ImmunoConcEpT, Bordeaux, France
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2
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Lotze MT, Olejniczak SH, Skokos D. CD28 co-stimulation: novel insights and applications in cancer immunotherapy. Nat Rev Immunol 2024; 24:878-895. [PMID: 39054343 PMCID: PMC11598642 DOI: 10.1038/s41577-024-01061-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/18/2024] [Indexed: 07/27/2024]
Abstract
Substantial progress in understanding T cell signalling, particularly with respect to T cell co-receptors such as the co-stimulatory receptor CD28, has been made in recent years. This knowledge has been instrumental in the development of innovative immunotherapies for patients with cancer, including immune checkpoint blockade antibodies, adoptive cell therapies, tumour-targeted immunostimulatory antibodies, and immunostimulatory small-molecule drugs that regulate T cell activation. Following the failed clinical trial of a CD28 superagonist antibody in 2006, targeted CD28 agonism has re-emerged as a technologically viable and clinically promising strategy for cancer immunotherapy. In this Review, we explore recent insights into the molecular functions and regulation of CD28. We describe how CD28 is central to the success of current cancer immunotherapies and examine how new questions arising from studies of CD28 as a clinical target have enhanced our understanding of its biological role and may guide the development of future therapeutic strategies in oncology.
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Affiliation(s)
- Michael T Lotze
- Department of Surgery, University of Pittsburgh Hillman Cancer Center, Pittsburgh, PA, USA.
- Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA.
- Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA.
| | - Scott H Olejniczak
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
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3
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Lioulios G, Fylaktou A, Xochelli A, Tourountzis T, Christodoulou M, Moysidou E, Stai S, Vagiotas L, Stangou M. Hemodiafiltration May Be Associated with Senescence-Related Phenotypic Alterations of Lymphocytes, Which May Predict Mortality in Patients Undergoing Dialysis. Int J Mol Sci 2024; 25:10925. [PMID: 39456708 PMCID: PMC11507245 DOI: 10.3390/ijms252010925] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Revised: 10/02/2024] [Accepted: 10/05/2024] [Indexed: 10/28/2024] Open
Abstract
Senescence-resembling alterations on the lymphocytes of patients undergoing dialysis have been widely described. However, the pathophysiology behind these phenomena has not been clarified. In this study, we examined the impact of dialysis prescription on T and B lymphocytes, in patients undergoing dialysis.: T and B cell subsets were determined with flow cytometry in 36 patients undergoing hemodialysis and 26 patients undergoing hemodiafiltration, according to the expression of CD45RA, CCR7, CD31, CD28, CD57, and PD1 for T cells, and IgD and CD27 for B cells. The immune phenotype was associated with dialysis modality, hemofiltration volume, and mortality. Compared with hemodialysis, patients undergoing hemodiafiltration had a significantly decreased percentage of CD4+CD28-CD57- T cells [3.8 (2.4-5.3) vs. 2.1 (1.3-3.3)%, respectively, p = 0.002] and exhausted CD4+ T cells [14.1 (8.9-19.4) vs. 8.5 (6.8-11.7)%, respectively, p = 0.005]. Additionally, the hemofiltration volume was negatively correlated with CD8+ EMRA T cells (r = -0.46, p = 0.03). Finally, the increased exhausted CD4+ T cell percentage was associated with increased all-cause mortality in patients undergoing dialysis, independent of age. Hemodiafiltration, especially with high hemofiltration volume, may have beneficial effects on senescence-related immune phenotypes. Immune phenotypes may also be a predicting factor for mortality in patients undergoing dialysis.
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Affiliation(s)
- Georgios Lioulios
- Department of Nephrology, 424 Military Hospital of Thessaloniki, 56429 Thessaloniki, Greece;
| | - Asimina Fylaktou
- Department of Immunology, National Peripheral Histocompatibility Center, General Hospital Hippokration, 54642 Thessaloniki, Greece; (A.F.); (A.X.)
| | - Aliki Xochelli
- Department of Immunology, National Peripheral Histocompatibility Center, General Hospital Hippokration, 54642 Thessaloniki, Greece; (A.F.); (A.X.)
| | | | - Michalis Christodoulou
- First Department of Nephrology, General Hospital Hippokration, 54642 Thessaloniki, Greece; (M.C.); (E.M.); (S.S.)
- School of Medicine, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece
| | - Eleni Moysidou
- First Department of Nephrology, General Hospital Hippokration, 54642 Thessaloniki, Greece; (M.C.); (E.M.); (S.S.)
- School of Medicine, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece
| | - Stamatia Stai
- First Department of Nephrology, General Hospital Hippokration, 54642 Thessaloniki, Greece; (M.C.); (E.M.); (S.S.)
- School of Medicine, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece
| | - Lampros Vagiotas
- Department of Transplant Surgery, General Hospital Hippokratio, 54642 Thessaloniki, Greece;
| | - Maria Stangou
- First Department of Nephrology, General Hospital Hippokration, 54642 Thessaloniki, Greece; (M.C.); (E.M.); (S.S.)
- School of Medicine, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece
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4
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Zhang T, Liu X, Zhao Y, Xu X, Liu Y, Wu X. Excessive IL-15 promotes cytotoxic CD4 + CD28- T cell-mediated renal injury in lupus nephritis. Immun Ageing 2022; 19:50. [PMID: 36320075 PMCID: PMC9624042 DOI: 10.1186/s12979-022-00305-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Revised: 08/28/2022] [Accepted: 10/10/2022] [Indexed: 11/22/2022]
Abstract
BACKGROUND Patients with systemic lupus erythematosus (SLE) are highly susceptible to infection and cardiovascular events, suggesting that chronic antigenic stimulation may accelerate premature aging in SLE patients. Premature aging in SLE is often accompanied with the expansion of cytotoxic CD4 + CD28-T cells. Damage caused by CD4 + CD28- T cells enhances the progressive aging of the tissue function and loss of organism's fitness. The high serum level of IL-15 has been implicated in the pathogenesis of SLE, but its role in CD4 + CD28-T cell-mediated cytotoxicity in nephritic SLE remains unclear. The aim of this study was to investigate the effect of IL-15 on functional properties and associated renal damage of cytotoxic CD4 + CD28- T cell in lupus nephritis (LN). RESULTS Flow cytometry showed that the number of circulating innate-like CD4 + CD28- T cells was increased in patients with nephritic SLE. Immunofluorescence showed CD4 + CD28- T cell infiltration in the kidney of LN patients, which was correlated with multiple clinicopathological features including estimated glomerular filtration rate (eGFR), proteinuria, the proportion of glomerulosclerosis and the degree of renal chronicity. In addition, a high level of IL-15 and IL15-expressing macrophage infiltration was detected in the periglomerular and intraglomerular tissues of LN patients, which enhanced the innate features, cytokine secretion and migratory capability of CD4 + CD28- T cells, and finally exerted direct TCR-independent cytotoxicity on glomerular endothelial cells in an IL-15-dependent manner in vitro. CONCLUSION Our study demonstrated that excessive IL-15 potentially promoted cytotoxic CD4 + CD28- T cell-mediated renal damage in LN. This finding may provide new insights into the potential association of premature aging and tissue damage in LN.
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Affiliation(s)
- Ti Zhang
- grid.41156.370000 0001 2314 964XJinling Hospital, National Clinical Research Center of Kidney Diseases, Nanjing University School of Medicine, Nanjing, China
| | - Xin Liu
- grid.73113.370000 0004 0369 1660Department of Rheumatology and Immunology, Shanghai Changzheng Hospital, The Second Military Medical University, Shanghai, China
| | - Yue Zhao
- grid.41156.370000 0001 2314 964XJinling Hospital, National Clinical Research Center of Kidney Diseases, Nanjing University School of Medicine, Nanjing, China
| | - Xiaodong Xu
- grid.41156.370000 0001 2314 964XJinling Hospital, National Clinical Research Center of Kidney Diseases, Nanjing University School of Medicine, Nanjing, China
| | - Yaoyang Liu
- grid.73113.370000 0004 0369 1660Department of Rheumatology and Immunology, Shanghai Changzheng Hospital, The Second Military Medical University, Shanghai, China
| | - Xin Wu
- grid.73113.370000 0004 0369 1660Department of Rheumatology and Immunology, Shanghai Changzheng Hospital, The Second Military Medical University, Shanghai, China
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5
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Vagiotas L, Stangou M, Kasimatis E, Xochelli A, Myserlis G, Lioulios G, Nikolaidou V, Panteli M, Ouranos K, Antoniadis N, Maria D, Papagianni A, Tsoulfas G, Fylaktou A. Effect of panel reactive antibodies on T cell immunity reinstatement following renal transplantation. World J Transplant 2022; 12:313-324. [PMID: 36313234 PMCID: PMC9614585 DOI: 10.5500/wjt.v12.i10.313] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Revised: 08/05/2022] [Accepted: 09/09/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Chronic kidney disease is associated with immunological disorders, presented as phenotypic alterations of T lymphocytes. These changes are expected to be restored after a successful renal transplantation; however, additional parameters may contribute to this process. AIM To evaluate the impact of positive panel reactive antibodies (PRAs) on the restoration of T cell phenotype, after renal transplantation. METHODS CD4CD28null, CD8CD28null, natural killer cells (NKs), and regulatory T cells (Tregs) were estimated by flow cytometry at T0, T3, and T6 which were the time of transplantation, and 3- and 6-mo follow-up, respectively. Changes were esti mated regarding the presence or absence of PRAs. RESULTS Patients were classified in two groups: PRA(-) (n = 43) and PRA(+) (n = 28) groups. Lymphocyte and their subtypes were similar between the two groups at T0, whereas their percentage was increased at T3 in PRA(-) compared to PRA(+) [23 (10.9-47.9) vs 16.4 (7.5-36.8 μ/L, respectively; P = 0.03]. Lymphocyte changes in PRA(-) patients included a significant increase in CD4 cells (P < 0.0001), CD8 cells (P < 0.0001), and Tregs (P < 0.0001), and a reduction of NKs (P < 0.0001). PRA(+) patients showed an increase in CD4 (P = 0.008) and CD8 (P = 0.0001), and a reduction in NKs (P = 0.07). CD4CD28null and CD8CD28null cells, although initially reduced in both groups, were stabilized thereafter. CONCLUSION Our study described important differences in the immune response between PRA(+) and PRA(-) patients with changes in lymphocytes and lymphocyte subpopulations. PRA(+) patients seemed to have a worse immune profile after 6 mo follow-up, regardless of renal function.
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Affiliation(s)
- Lampros Vagiotas
- Department of Transplant Surgery, School of Medicine, Aristotle University of Thessaloniki, Hippokration General Hospital, Thessaloniki 54642, Greece
| | - Maria Stangou
- Department of Nephrology, School of Medicine, Aristotle University of Thessaloniki, Hippokration General Hospital, Thessaloniki 54642, Greece
| | - Efstratios Kasimatis
- Department of Nephrology, School of Medicine, Aristotle University of Thessaloniki, Hippokration General Hospital, Thessaloniki 54642, Greece
| | - Aliki Xochelli
- Department of Immunology, National Peripheral Histocompatibility Center, Hippokration General Hospital, Thessaloniki 54642, Greece
| | - Grigorios Myserlis
- Department of Transplant Surgery, School of Medicine, Aristotle University of Thessaloniki, Hippokration General Hospital, Thessaloniki 54642, Greece
| | - Georgios Lioulios
- Department of Nephrology, School of Medicine, Aristotle University of Thessaloniki, Hippokration General Hospital, Thessaloniki 54642, Greece
| | - Vasiliki Nikolaidou
- Department of Immunology, National Peripheral Histocompatibility Center, Hippokration General Hospital, Thessaloniki 54642, Greece
| | - Manolis Panteli
- Department of Nephrology, School of Medicine, Aristotle University of Thessaloniki, Hippokration General Hospital, Thessaloniki 54642, Greece
| | - Konstantinos Ouranos
- Department of Nephrology, School of Medicine, Aristotle University of Thessaloniki, Hippokration General Hospital, Thessaloniki 54642, Greece
| | - Nikolaos Antoniadis
- Department of Transplant Surgery, School of Medicine, Aristotle University of Thessaloniki, Hippokration General Hospital, Thessaloniki 54642, Greece
| | - Daoudaki Maria
- Medical School Aristotle University of Thessaloniki, Biochemistry Laboratory, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece
| | - Aikaterini Papagianni
- Department of Nephrology, School of Medicine, Aristotle University of Thessaloniki, Hippokration General Hospital, Thessaloniki 54642, Greece
| | - Georgios Tsoulfas
- Department of Transplant Surgery, School of Medicine, Aristotle University of Thessaloniki, Hippokration General Hospital, Thessaloniki 54642, Greece
| | - Asimina Fylaktou
- Department of Immunology, National Peripheral Histocompatibility Center, Hippokration General Hospital, Thessaloniki 54642, Greece
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6
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Witkowski JM, Fulop T, Bryl E. Immunosenescence and COVID-19. Mech Ageing Dev 2022; 204:111672. [PMID: 35378106 PMCID: PMC8975602 DOI: 10.1016/j.mad.2022.111672] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 03/28/2022] [Accepted: 03/29/2022] [Indexed: 12/13/2022]
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González-Osuna L, Sierra-Cristancho A, Cafferata EA, Melgar-Rodríguez S, Rojas C, Carvajal P, Cortez C, Vernal R. Senescent CD4 +CD28 - T Lymphocytes as a Potential Driver of Th17/Treg Imbalance and Alveolar Bone Resorption during Periodontitis. Int J Mol Sci 2022; 23:ijms23052543. [PMID: 35269683 PMCID: PMC8910032 DOI: 10.3390/ijms23052543] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 02/19/2022] [Accepted: 02/22/2022] [Indexed: 01/10/2023] Open
Abstract
Senescent cells express a senescence-associated secretory phenotype (SASP) with a pro-inflammatory bias, which contributes to the chronicity of inflammation. During chronic inflammatory diseases, infiltrating CD4+ T lymphocytes can undergo cellular senescence and arrest the surface expression of CD28, have a response biased towards T-helper type-17 (Th17) of immunity, and show a remarkable ability to induce osteoclastogenesis. As a cellular counterpart, T regulatory lymphocytes (Tregs) can also undergo cellular senescence, and CD28− Tregs are able to express an SASP secretome, thus severely altering their immunosuppressive capacities. During periodontitis, the persistent microbial challenge and chronic inflammation favor the induction of cellular senescence. Therefore, senescence of Th17 and Treg lymphocytes could contribute to Th17/Treg imbalance and favor the tooth-supporting alveolar bone loss characteristic of the disease. In the present review, we describe the concept of cellular senescence; particularly, the one produced during chronic inflammation and persistent microbial antigen challenge. In addition, we detail the different markers used to identify senescent cells, proposing those specific to senescent T lymphocytes that can be used for periodontal research purposes. Finally, we discuss the existing literature that allows us to suggest the potential pathogenic role of senescent CD4+CD28− T lymphocytes in periodontitis.
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Affiliation(s)
- Luis González-Osuna
- Periodontal Biology Laboratory, Faculty of Dentistry, Universidad de Chile, Santiago 8380492, Chile; (A.S.-C.); (E.A.C.); (S.M.-R.); (C.R.)
- Correspondence: (L.G.-O.); (R.V.)
| | - Alfredo Sierra-Cristancho
- Periodontal Biology Laboratory, Faculty of Dentistry, Universidad de Chile, Santiago 8380492, Chile; (A.S.-C.); (E.A.C.); (S.M.-R.); (C.R.)
- Faculty of Dentistry, Universidad Andres Bello, Santiago 8370035, Chile
| | - Emilio A. Cafferata
- Periodontal Biology Laboratory, Faculty of Dentistry, Universidad de Chile, Santiago 8380492, Chile; (A.S.-C.); (E.A.C.); (S.M.-R.); (C.R.)
- Department of Periodontology, School of Dentistry, Universidad Científica del Sur, Lima 15067, Peru
| | - Samanta Melgar-Rodríguez
- Periodontal Biology Laboratory, Faculty of Dentistry, Universidad de Chile, Santiago 8380492, Chile; (A.S.-C.); (E.A.C.); (S.M.-R.); (C.R.)
- Department of Conservative Dentistry, Faculty of Dentistry, Universidad de Chile, Santiago 8380492, Chile;
| | - Carolina Rojas
- Periodontal Biology Laboratory, Faculty of Dentistry, Universidad de Chile, Santiago 8380492, Chile; (A.S.-C.); (E.A.C.); (S.M.-R.); (C.R.)
| | - Paola Carvajal
- Department of Conservative Dentistry, Faculty of Dentistry, Universidad de Chile, Santiago 8380492, Chile;
| | - Cristian Cortez
- Center for Genomics and Bioinformatics, Faculty of Sciences, Universidad Mayor, Santiago 8580745, Chile;
| | - Rolando Vernal
- Periodontal Biology Laboratory, Faculty of Dentistry, Universidad de Chile, Santiago 8380492, Chile; (A.S.-C.); (E.A.C.); (S.M.-R.); (C.R.)
- Department of Conservative Dentistry, Faculty of Dentistry, Universidad de Chile, Santiago 8380492, Chile;
- Correspondence: (L.G.-O.); (R.V.)
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8
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Witkowski JM. Immune system aging and the aging-related diseases in the COVIID-19 era. Immunol Lett 2022; 243:19-27. [PMID: 35108570 PMCID: PMC8801734 DOI: 10.1016/j.imlet.2022.01.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 01/26/2022] [Accepted: 01/29/2022] [Indexed: 12/13/2022]
Abstract
The interest in the process of aging, and specifically in how aging affects the working of our immune system, has recently enormously grown among both specialists (immunologists and gerontologists) and representatives of other disciplines of health sciences. An obvious reason for this interest is the current pandemics of COVID-19, known to affect the elderly more than younger people. In this paper current knowledge about mechanisms and complex facets of human immune system aging is presented, stemming from the knowledge about the working of various parts of the immune system, and leading to understanding of immunological mechanisms of chronic, inflammatory, aging-related diseases and of COVID-19.
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Affiliation(s)
- Jacek M Witkowski
- Department of Pathophysiology, Medical University of Gdańsk, Dębinki 7, 80-211, Gdańsk, Poland.
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9
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Lioulios G, Fylaktou A, Papagianni A, Stangou M. T cell markers recount the course of immunosenescence in healthy individuals and chronic kidney disease. Clin Immunol 2021; 225:108685. [PMID: 33549833 DOI: 10.1016/j.clim.2021.108685] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2020] [Revised: 01/18/2021] [Accepted: 02/02/2021] [Indexed: 12/12/2022]
Abstract
Aging results in substantial changes in almost all cellular subpopulations within the immune system, including functional and phenotypic alterations. T lymphocytes, as the main representative population of cellular immunity, have been extensively studied in terms of modifications and adjustments during aging. Phenotypic alterations are attributed to three main mechanisms; a reduction of naïve T cell population with a shift to more differentiated forms, a subsequent oligoclonal expansion of naïve T cells characterized by repertoire restriction, and replicative insufficiency after repetitive activation. These changes and the subsequent phenotypic disorders are comprised in the term "immunosenescence". Similar changes seem to occur in chronic kidney disease, with T cells of young patients resembling those of healthy older individuals. A broad range of surface markers can be utilized to identify immunosenescent T cells. In this review, we will discuss the most important senescence markers and their potential connection with impaired renal function.
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Affiliation(s)
- Georgios Lioulios
- Department of Nephrology, Aristotle University of Thessaloniki, Hippokration Hospital, Thessaloniki, Greece.
| | - Asimina Fylaktou
- Department of Immunology, National Peripheral Histocompatibility Center, Hippokration Hospital, Thessaloniki, Greece
| | - Aikaterini Papagianni
- Department of Nephrology, Aristotle University of Thessaloniki, Hippokration Hospital, Thessaloniki, Greece
| | - Maria Stangou
- Department of Nephrology, Aristotle University of Thessaloniki, Hippokration Hospital, Thessaloniki, Greece
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10
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Russell DL, Oates JC, Markiewicz M. Association Between the Anti-Aging Gene Klotho and Selected Rheumatologic Autoimmune Diseases. Am J Med Sci 2021; 361:169-175. [PMID: 33349438 PMCID: PMC9741923 DOI: 10.1016/j.amjms.2020.10.021] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Revised: 08/25/2020] [Accepted: 10/22/2020] [Indexed: 12/14/2022]
Abstract
Klotho long recognized for its role in anti-aging, is potentially implicated in the pathogenesis of rheumatoid arthritis, systemic lupus erythematosus, and systemic sclerosis. Aging of the immune system coincides with the inability of the body to recognize self-antigens, which often leads to autoimmune responses. The role of Klotho in these autoimmune diseases should be of high interest; however, few articles have been published exploring the role of Klotho in the pathogenesis, organ involvement, or clinical manifestation of rheumatoid arthritis, systemic lupus erythematosus, and systemic sclerosis. Herein, we discuss information gathered from peer-reviewed publications to describe the emerging role of Kl in these select rheumatologic autoimmune diseases.
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Affiliation(s)
| | - Jim C Oates
- Ralph H. Johnson VA Medical Center, Charleston, South Carolina;,Division of Rheumatology and Immunology, Medical University of South Carolina, Charleston, South Carolina
| | - Margaret Markiewicz
- Division of Rheumatology and Immunology, Medical University of South Carolina, Charleston, South Carolina
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11
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Luque-Campos N, Contreras-López RA, Jose Paredes-Martínez M, Torres MJ, Bahraoui S, Wei M, Espinoza F, Djouad F, Elizondo-Vega RJ, Luz-Crawford P. Mesenchymal Stem Cells Improve Rheumatoid Arthritis Progression by Controlling Memory T Cell Response. Front Immunol 2019; 10:798. [PMID: 31040848 PMCID: PMC6477064 DOI: 10.3389/fimmu.2019.00798] [Citation(s) in RCA: 90] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Accepted: 03/26/2019] [Indexed: 12/14/2022] Open
Abstract
In the last years, mesenchymal stem cell (MSC)-based therapies have become an interesting therapeutic opportunity for the treatment of rheumatoid arthritis (RA) due to their capacity to potently modulate the immune response. RA is a chronic autoimmune inflammatory disorder with an incompletely understood etiology. However, it has been well described that peripheral tolerance defects and the subsequent abnormal infiltration and activation of diverse immune cells into the synovial membrane, are critical for RA development and progression. Moreover, the imbalance between the immune response of pro-inflammatory and anti-inflammatory cells, in particular between memory Th17 and memory regulatory T cells (Treg), respectively, is well admitted to be associated to RA immunopathogenesis. In this context, MSCs, which are able to alter the frequency and function of memory lymphocytes including Th17, follicular helper T (Tfh) cells and gamma delta (γδ) T cells while promoting Treg cell generation, have been proposed as a candidate of choice for RA cell therapy. Indeed, given the plasticity of memory CD4+ T cells, it is reasonable to think that MSCs will restore the balance between pro-inflammatory and anti-inflammatory memory T cells populations deregulated in RA leading to prompt their therapeutic function. In the present review, we will discuss the role of memory T cells implicated in RA pathogenesis and the beneficial effects exerted by MSCs on the phenotype and functions of these immune cells abnormally regulated in RA and how this regulation could impact RA progression.
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Affiliation(s)
- Noymar Luque-Campos
- Laboratorio de Inmunología Celular y Molecular, Centro de Investigación Biomédica, Facultad de Medicina, Universidad de los Andes, Santiago, Chile
| | - Rafael A Contreras-López
- Laboratorio de Inmunología Celular y Molecular, Centro de Investigación Biomédica, Facultad de Medicina, Universidad de los Andes, Santiago, Chile
| | - María Jose Paredes-Martínez
- Laboratorio de Inmunología Celular y Molecular, Centro de Investigación Biomédica, Facultad de Medicina, Universidad de los Andes, Santiago, Chile
| | - Maria Jose Torres
- Escuela de Ingeniería Bioquímica, Pontificia Universidad Católica de Valparaíso, Valparaíso, Chile
| | | | - Mingxing Wei
- Cellvax, SAS, Parc BIOCITECH, Romainville, France
| | | | | | - Roberto Javier Elizondo-Vega
- Laboratorio de Biología Celular, Departamento de Biología Celular, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile
| | - Patricia Luz-Crawford
- Laboratorio de Inmunología Celular y Molecular, Centro de Investigación Biomédica, Facultad de Medicina, Universidad de los Andes, Santiago, Chile
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12
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Witkowski JM, Mikosik A, Bryl E, Fulop T. Proteodynamics in aging human T cells - The need for its comprehensive study to understand the fine regulation of T lymphocyte functions. Exp Gerontol 2017; 107:161-168. [PMID: 29038026 DOI: 10.1016/j.exger.2017.10.009] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2017] [Revised: 10/01/2017] [Accepted: 10/09/2017] [Indexed: 12/20/2022]
Abstract
Cellular life depends mostly on the creation, modification, interactions and destruction of proteins. This is true for every cell, including human T lymphocytes. One way these cells can ascertain the fidelity and at least partial functionality of their proteomes under constant attack of irreversible modulations (e.g., ROS- or glycation-dependent) is proteostasis. However, with cellular aging proteostasis progressively fails and proteostenosis (decreased amounts and functionalities of remaining proteins) occurs. There are several mechanisms involved in the modulation and protection of the proteome in the T cells which include mainly multiple layers of vesicle-bound and cytoplasmic proteases (e.g., lysosomal and proteasomal ones) acting mostly by degradation of obsolete and age-modified proteins. Recently it was shown that another not yet so widely known system consisting of obligatorily calcium-dependent cysteine proteases, the calpains and their inhibitor, the calpastatin serves in T cells as a dual switch, either activating or inactivating different proteins depending on intracellular conditions. Thus the proteolytic elimination of altered proteins as well as modulation of activity of those remaining leads to dynamic change of proteome composition and function (proteodynamics) in aging lymphocytes, so far in an almost unknown way. Aging T cell proteodynamics requires further comprehensive analysis of the resulting lysoproteomic patterns and their changes.
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Affiliation(s)
- Jacek M Witkowski
- Department of Pathophysiology, Medical University of Gdańsk, Poland.
| | - Anna Mikosik
- Department of Pathophysiology, Medical University of Gdańsk, Poland
| | - Ewa Bryl
- Department of Pathology and Experimental Rheumatology, Medical University of Gdańsk, Poland
| | - Tamas Fulop
- Centre for Aging Research, University of Sherbrooke, QC, Canada
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13
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Kyaw T, Peter K, Li Y, Tipping P, Toh BH, Bobik A. Cytotoxic lymphocytes and atherosclerosis: significance, mechanisms and therapeutic challenges. Br J Pharmacol 2017; 174:3956-3972. [PMID: 28471481 DOI: 10.1111/bph.13845] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2016] [Revised: 04/02/2017] [Accepted: 04/24/2017] [Indexed: 02/06/2023] Open
Abstract
Cytotoxic lymphocytes encompass natural killer lymphocytes (cells) and cytotoxic T cells that include CD8+ T cells, natural killer (NK) T cells, γ, δ (γδ)-T cells and human CD4 + CD28- T cells. These cells play critical roles in inflammatory diseases and in controlling cancers and infections. Cytotoxic lymphocytes can be activated via a number of mechanisms that may involve dendritic cells, macrophages, cytokines or surface proteins on stressed cells. Upon activation, they secrete pro-inflammatory cytokines as well as anti-inflammatory cytokines, chemokines and cytotoxins to promote inflammation and the development of atherosclerotic lesions including vulnerable lesions, which are strongly implicated in myocardial infarctions and strokes. Here, we review the mechanisms that activate and regulate cytotoxic lymphocyte activity, including activating and inhibitory receptors, cytokines, chemokine receptors-chemokine systems utilized to home to inflamed lesions and cytotoxins and cytokines through which they affect other cells within lesions. We also examine their roles in human and mouse models of atherosclerosis and the mechanisms by which they exert their pathogenic effects. Finally, we discuss strategies for therapeutically targeting these cells to prevent the development of atherosclerotic lesions and vulnerable plaques and the challenge of developing highly targeted therapies that only minimally affect the body's immune system, avoiding the complications, such as increased susceptibility to infections, which are currently associated with many immunotherapies for autoimmune diseases. LINKED ARTICLES This article is part of a themed section on Targeting Inflammation to Reduce Cardiovascular Disease Risk. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.22/issuetoc and http://onlinelibrary.wiley.com/doi/10.1111/bcp.v82.4/issuetoc.
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Affiliation(s)
- Tin Kyaw
- Baker Heart and Diabetes Institute, Melbourne, Vic, Australia.,Department of Medicine, Monash University, Melbourne, Vic, Australia
| | - Karlheinz Peter
- Baker Heart and Diabetes Institute, Melbourne, Vic, Australia.,Department of Immunology, Monash University, Melbourne, Vic, Australia
| | - Yi Li
- Baker Heart and Diabetes Institute, Melbourne, Vic, Australia.,Department of Medicine, Monash University, Melbourne, Vic, Australia
| | - Peter Tipping
- Department of Medicine, Monash University, Melbourne, Vic, Australia
| | - Ban-Hock Toh
- Baker Heart and Diabetes Institute, Melbourne, Vic, Australia.,Department of Medicine, Monash University, Melbourne, Vic, Australia
| | - Alex Bobik
- Baker Heart and Diabetes Institute, Melbourne, Vic, Australia.,Department of Immunology, Monash University, Melbourne, Vic, Australia.,Department of Medicine, Monash University, Melbourne, Vic, Australia
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14
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Suarez-Álvarez B, Rodríguez RM, Schlangen K, Raneros AB, Márquez-Kisinousky L, Fernández AF, Díaz-Corte C, Aransay AM, López-Larrea C. Phenotypic characteristics of aged CD4 + CD28 null T lymphocytes are determined by changes in the whole-genome DNA methylation pattern. Aging Cell 2017; 16:293-303. [PMID: 28026094 PMCID: PMC5334526 DOI: 10.1111/acel.12552] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/31/2016] [Indexed: 01/01/2023] Open
Abstract
Aging is associated with a progressive loss of the CD28 costimulatory molecule in CD4+ lymphocytes (CD28null T cells), which is accompanied by the acquisition of new biological and functional properties that give rise to an impaired immune response. The regulatory mechanisms that govern the appearance and function of this cell subset during aging and in several associated inflammatory disorders remain controversial. Here, we present the whole‐genome DNA methylation and gene expression profiles of CD28null T cells and its CD28+ counterpart. A comparative analysis revealed that 296 genes are differentially methylated between the two cell subsets. A total of 160 genes associated with cytotoxicity (e.g. GRZB,TYROBP, and RUNX3) and cytokine/chemokine signaling (e.g. CX3CR1,CD27, and IL‐1R) are demethylated in CD28null T cells, while 136 de novo‐methylated genes matched defects in the TCR signaling pathway (e.g. ITK,TXK,CD3G, and LCK). TCR‐landscape analysis confirmed that CD28null T cells have an oligo/monoclonal expansion over the polyclonal background of CD28+ T cells, but feature a Vβ family repertoire specific to each individual. We reported that CD28null T cells show a preactivation state characterized by a higher level of expression of inflammasome‐related genes that leads to the release of IL‐1β when activated. Overall, our results demonstrate that CD28null T cells have a unique DNA methylation landscape, which is associated with differences in gene expression, contributing to the functionality of these cells. Understanding these epigenetic regulatory mechanisms could suggest novel therapeutic strategies to prevent the accumulation and activation of these cells during aging.
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Affiliation(s)
| | - Ramón M. Rodríguez
- Department of Immunology; Hospital Universitario Central de Asturias; Oviedo Spain
| | - Karin Schlangen
- Genome Analysis Platform; CIC bioGUNE; Bizkaia Technological Technology Park; Derio Spain
| | | | | | - Agustín F. Fernández
- Cancer Epigenetics Laboratory; Institute of Oncology of Asturias (IUOPA); Hospital Universitario Central de Asturias; Oviedo Spain
| | - Carmen Díaz-Corte
- Department of Nephrology; Hospital Universitario Central de Asturias; Oviedo Spain
| | - Ana M. Aransay
- Genome Analysis Platform; CIC bioGUNE; Bizkaia Technological Technology Park; Derio Spain
- CIBERhed
| | - Carlos López-Larrea
- Department of Immunology; Hospital Universitario Central de Asturias; Oviedo Spain
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15
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Lee GH, Lee WW. Unusual CD4 +CD28 - T Cells and Their Pathogenic Role in Chronic Inflammatory Disorders. Immune Netw 2016; 16:322-329. [PMID: 28035207 PMCID: PMC5195841 DOI: 10.4110/in.2016.16.6.322] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2016] [Revised: 09/23/2016] [Accepted: 09/30/2016] [Indexed: 12/17/2022] Open
Abstract
CD28 is a primary co-stimulatory receptor that is essential for successful T cell activation, proliferation, and survival. While ubiquitously expressed on naive T cells, the level of CD28 expression on memory T cells is largely dependent on the T-cell differentiation stage in humans. Expansion of circulating T cells lacking CD28 was originally considered a hallmark of age-associated immunological changes in humans, with a progressive loss of CD28 following replicative senescence with advancing age. However, an increasing body of evidence has revealed that there is a significant age-inappropriate expansion of CD4+CD28− T cells in patients with a variety of chronic inflammatory diseases, suggesting that these cells play a role in their pathogenesis. In fact, expanded CD4+CD28− T cells can produce large amounts of proinflammatory cytokines such as IFN-γ and TNF-α and also have cytotoxic potential, which may cause tissue damage and development of pathogenesis in many inflammatory disorders. Here we review the characteristics of CD4+CD28− T cells as well as the recent advances highlighting the contribution of these cells to several disease conditions.
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Affiliation(s)
- Ga Hye Lee
- Department of Biomedical Sciences, Seoul National University College of Medicine and BK21Plus Biomedical Science Project, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Won-Woo Lee
- Department of Biomedical Sciences, Seoul National University College of Medicine and BK21Plus Biomedical Science Project, Seoul National University College of Medicine, Seoul 03080, Korea.; Department of Microbiology and Immunology, Seoul National University College of Medicine; Ischemic/Hypoxic Disease Institute and Institute of Infectious Diseases, Seoul National University College of Medicine; Seoul National University Hospital Biomedical Research Institute, Seoul 03080, Korea
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16
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Michel JJ, Griffin P, Vallejo AN. Functionally Diverse NK-Like T Cells Are Effectors and Predictors of Successful Aging. Front Immunol 2016; 7:530. [PMID: 27933066 PMCID: PMC5121286 DOI: 10.3389/fimmu.2016.00530] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Accepted: 11/10/2016] [Indexed: 12/16/2022] Open
Abstract
The fundamental challenge of aging and long-term survivorship is maintenance of functional independence and compression of morbidity despite a life history of disease. Inasmuch as immunity is a determinant of individual health and fitness, unraveling novel mechanisms of immune homeostasis in late life is of paramount interest. Comparative studies of young and old persons have documented age-related atrophy of the thymus, the contraction of diversity of the T cell receptor (TCR) repertoire, and the intrinsic inefficiency of classical TCR signaling in aged T cells. However, the elderly have highly heterogeneous health phenotypes. Studies of defined populations of persons aged 75 and older have led to the recognition of successful aging, a distinct physiologic construct characterized by high physical and cognitive functioning without measurable disability. Significantly, successful agers have a unique T cell repertoire; namely, the dominance of highly oligoclonal αβT cells expressing a diverse array of receptors normally expressed by NK cells. Despite their properties of cell senescence, these unusual NK-like T cells are functionally active effectors that do not require engagement of their clonotypic TCR. Thus, NK-like T cells represent a beneficial remodeling of the immune repertoire with advancing age, consistent with the concept of immune plasticity. Significantly, certain subsets are predictors of physical/cognitive performance among older adults. Further understanding of the roles of these NK-like T cells to host defense, and how they integrate with other physiologic domains of function are new frontiers for investigation in Aging Biology. Such pursuits will require a research paradigm shift from the usual young-versus-old comparison to the analysis of defined elderly populations. These endeavors may also pave way to age-appropriate, group-targeted immune interventions for the growing elderly population.
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Affiliation(s)
- Joshua J Michel
- Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Patricia Griffin
- Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Abbe N Vallejo
- Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Pittsburgh Claude Pepper Older Americans Independence Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
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17
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Marciani DJ. A retrospective analysis of the Alzheimer's disease vaccine progress - The critical need for new development strategies. J Neurochem 2016; 137:687-700. [PMID: 26990863 DOI: 10.1111/jnc.13608] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2016] [Revised: 02/25/2016] [Accepted: 02/26/2016] [Indexed: 12/16/2022]
Abstract
The promising results obtained with aducanumab and solanezumab against Alzheimer's disease (AD) strengthen the vaccine approach to prevent AD, despite of the many clinical setbacks. It has been problematic to use conjugated peptides with Th1/Th2 adjuvants to induce immune responses against conformational epitopes formed by Aβ oligomers, which is critical to induce protective antibodies. Hence, vaccination should mimic natural immunity by using whole or if possible conjugated antigens, but biasing the response to Th2 with anti-inflammatory adjuvants. Also, selection of the carrier and cross-linking agents is important to prevent suppression of the immune response against the antigen. That certain compounds having phosphorylcholine or fucose induce a sole Th2 immunity would allow antigens with T-cell epitopes without inflammatory autoimmune reactions to be used. Another immunization method is DNA vaccines combined with antigenic ones, which favors the clonal selection and expansion of high affinity antibodies needed for immune protection, but this also requires Th2 immunity. Since AD transgenic mouse models have limited value for immunogen selection as shown by the clinical studies, screening may require the use of validated antibodies and biophysical methods to identify the antigens that would be most likely recognized by the human immune system and thus capable to stimulate a protective antibody response. To induce an anti-Alzheimer's disease protective immunity and prevent possible damage triggered by antigens having B-cell epitopes-only, whole antigens might be used; while inducing Th2 immunity with sole anti-inflammatory fucose-based adjuvants. This approach would avert a damaging systemic inflammatory immunity and the suppression of immunoresponse against the antigen because of carrier and cross-linkers; immune requirements that extend to DNA vaccines.
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18
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Betjes MGH. Clinical consequences of circulating CD28-negative T cells for solid organ transplantation. Transpl Int 2015; 29:274-84. [DOI: 10.1111/tri.12658] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2015] [Revised: 07/06/2015] [Accepted: 08/11/2015] [Indexed: 12/14/2022]
Affiliation(s)
- Michiel G. H. Betjes
- Department of Nephrology and Transplantation; Erasmus Medical Center; Rotterdam the Netherlands
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19
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The story of CD4+ CD28- T cells revisited: solved or still ongoing? J Immunol Res 2015; 2015:348746. [PMID: 25834833 PMCID: PMC4365319 DOI: 10.1155/2015/348746] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2014] [Revised: 02/10/2015] [Accepted: 02/19/2015] [Indexed: 02/07/2023] Open
Abstract
CD4+CD28− T cells are a unique type of proinflammatory T cells characterised by blockade of costimulatory CD28 receptor expression at the transcriptional level, which is still reversible by IL-12. In healthy individuals older than 65 years, these cells may accumulate to up to 50% of total CD4+ T lymphocytes as in many immune-mediated diseases, immunodeficiency, and specific infectious diseases. Here we focus on CD4+CD28− T cells in chronic immune-mediated diseases, summarizing various phenotypic and functional characteristics, which vary depending on the underlying disease, disease activity, and concurrent treatment. CD4+CD28− T cells present as effector/memory cells with increased replicative history and oligoclonality but reduced apoptosis. As an alternative costimulatory signal instead of CD28, not only natural killer cell receptors and Toll-like receptors, but also CD47, CTLA-4, OX40, and 4-1BB have to be considered. The proinflammatory and cytotoxic capacities of these cells indicate an involvement in progression and maintenance of chronic immune-mediated disease. So far it has been shown that treatment with TNF-α blockers, abatacept, statins, and polyclonal antilymphocyte globulins (ATG) mediates reduction of the CD4+CD28− T cell level. The clinical relevance of targeting CD4+CD28− T cells as a therapeutic option has not been examined so far.
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20
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Torrão RC, Bennett SJ, Brown JE, Griffiths HR. Does metabolic reprogramming underpin age-associated changes in T cell phenotype and function? Free Radic Biol Med 2014; 71:26-35. [PMID: 24632379 DOI: 10.1016/j.freeradbiomed.2014.03.002] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2013] [Revised: 03/02/2014] [Accepted: 03/04/2014] [Indexed: 01/01/2023]
Abstract
T cells are required for an effective adaptive immune response. The principal function of T cells is to promote efficient removal of foreign material by identifying and mounting a specific response to nonself. A decline in T cell function in aging is thought to contribute to reduced response to infection and vaccination and an increase in autoimmunity. This may in part be due to the age-related decrease in naïve CD4(+) T cells and increase in antigen-experienced CD4(+) T cells, loss of redox homeostasis, and impaired metabolic switching. Switching between subsets is triggered by the integration of extracellular signals sensed through surface receptors and the activation of discrete intracellular metabolic pathways. This article explores how metabolic programming and loss of redox homeostasis during aging may contribute to age-associated changes in T cell phenotype and function.
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Affiliation(s)
- Rita C Torrão
- Life and Health Sciences and Aston Research Centre for Healthy Ageing, Aston University, Birmingham B4 7ET, West Midlands, UK
| | - Stuart J Bennett
- Life and Health Sciences and Aston Research Centre for Healthy Ageing, Aston University, Birmingham B4 7ET, West Midlands, UK
| | - James E Brown
- Life and Health Sciences and Aston Research Centre for Healthy Ageing, Aston University, Birmingham B4 7ET, West Midlands, UK
| | - Helen R Griffiths
- Life and Health Sciences and Aston Research Centre for Healthy Ageing, Aston University, Birmingham B4 7ET, West Midlands, UK.
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21
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Pieper J, Johansson S, Snir O, Linton L, Rieck M, Buckner JH, Winqvist O, van Vollenhoven R, Malmström V. Peripheral and site-specific CD4(+) CD28(null) T cells from rheumatoid arthritis patients show distinct characteristics. Scand J Immunol 2014; 79:149-55. [PMID: 24313359 DOI: 10.1111/sji.12139] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2013] [Accepted: 11/19/2013] [Indexed: 12/28/2022]
Abstract
Proinflammatory CD4(+) CD28(null) T cells are frequently found in the circulation of patients with rheumatoid arthritis (RA), but are less common in the rheumatic joint. In the present study, we sought to identify functional differences between CD4(+) CD28(null) T cells from blood and synovial fluid in comparison with conventional CD28-expressing CD4(+) T cells. Forty-four patients with RA, displaying a distinct CD4(+) CD28(null) T cell population in blood, were recruited for this study; the methylation status of the IFNG locus was examined in isolated T cell subsets, and intracellular cytokine production (IFN-γ, TNF, IL-17) and chemokine receptor expression (CXCR3, CCR6 and CCR7) were assessed by flow cytometry on T cells from the two compartments. Circulating CD4(+) CD28(null) T cells were significantly more hypomethylated in the CNS-1 region of the IFNG locus than conventional CD4(+) CD28(+) T cells and produced higher levels of both IFN-γ and TNF after TCR cross-linking. CD4(+) CD28(null) T cells from the site of inflammation expressed significantly more CXCR3 and CCR6 compared to their counterparts in blood. While IL-17A production could hardly be detected in CD4(+) CD28(null) cells from the blood, a significant production was observed in CD4(+) CD28(null) T cells from synovial fluid. CD4(+) CD28(null) T cells were not only found to differ from conventional CD4(+) CD28(+) T cells in the circulation, but we could also demonstrate that synovial CD4(+) CD28(null) T cells showed additional effector functions (IL-17 coproduction) as compared to the same subset in peripheral blood, suggesting an active role for these cells in the perpetuation of inflammation in the subset of patients having a CD28(null) population.
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Affiliation(s)
- J Pieper
- Rheumatology Unit, Department of Medicine at Karolinska University Hospital, Karolinska Institute, Solna, Stockholm, Sweden
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22
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Carilho Torrao RBD, Dias IH, Bennett SJ, Dunston CR, Griffiths HR. Healthy ageing and depletion of intracellular glutathione influences T cell membrane thioredoxin-1 levels and cytokine secretion. Chem Cent J 2013; 7:150. [PMID: 24007191 PMCID: PMC3766689 DOI: 10.1186/1752-153x-7-150] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2013] [Accepted: 08/14/2013] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND During ageing an altered redox balance has been observed in both intracellular and extracellular compartments, primarily due to glutathione depletion and metabolic stress. Maintaining redox homeostasis is important for controlling proliferation and apoptosis in response to specific stimuli for a variety of cells. For T cells, the ability to generate specific response to antigen is dependent on the oxidation state of cell surface and cytoplasmic protein-thiols. Intracellular thiols are maintained in their reduced state by a network of redox regulating peptides, proteins and enzymes such as glutathione, thioredoxins and thioredoxin reductase. Here we have investigated whether any relationship exists between age and secreted or cell surface thioredoxin-1, intracellular glutathione concentration and T cell surface thioredoxin 1 (Trx-1) and how this is related to interleukin (IL)-2 production. RESULTS Healthy older adults have reduced lymphocyte surface expression and lower circulating plasma Trx-1 concentrations. Using buthionine sulfoximine to deplete intracellular glutathione in Jurkat T cells we show that cell surface Trx-1 is lowered, secretion of Trx-1 is decreased and the response to the lectin phytohaemagglutinin measured as IL-2 production is also affected. These effects are recapitulated by another glutathione depleting agent, diethylmaleate. CONCLUSION Together these data suggest that a relationship exists between the intracellular redox compartment and Trx-1 proteins. Loss of lymphocyte surface Trx-1 may be a useful biomarker of healthy ageing.
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23
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Boots AMH, Maier AB, Stinissen P, Masson P, Lories RJ, De Keyser F. The influence of ageing on the development and management of rheumatoid arthritis. Nat Rev Rheumatol 2013; 9:604-13. [PMID: 23774902 DOI: 10.1038/nrrheum.2013.92] [Citation(s) in RCA: 89] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The population of elderly individuals with rheumatoid arthritis (RA) is expanding, due mainly to increasing life expectancy. A variety of theories have been proposed to explain the ageing process, including accumulation of DNA damage and resultant changes in biological processes. Such changes can influence the development and/or course of disease. Furthermore, alterations in biological function determine the biological age-as opposed to chronological age-of an individual, which strongly influences their ability to cope with disease. Moreover, comorbidities are more frequent in elderly individuals. Together, these factors complicate treatment of disease and necessitate careful patient management. Indeed, although evidence from clinical trials suggests that DMARDs and biologic agents have good efficacy and are well tolerated in elderly patients with RA, such individuals are often undertreated and inadequately managed. Unfortunately, insufficient data are available for the development of evidence-based guidelines for this population, as elderly patients are often excluded from clinical trials owing to age restrictions or comorbidities. Thus, additional clinical studies in elderly patients are warranted, with treatment regimens tailored according to vitality or frailty parameters. This Review focuses on the pathophysiological aspects of ageing and their implications for the management of RA in elderly patients.
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Affiliation(s)
- Annemieke M H Boots
- Department of Rheumatology and Clinical Immunology, UMCG, University of Groningen, 9700 RB, Groningen, The Netherlands
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Moro-García MA, Alonso-Arias R, López-Larrea C. Molecular mechanisms involved in the aging of the T-cell immune response. Curr Genomics 2013; 13:589-602. [PMID: 23730199 PMCID: PMC3492799 DOI: 10.2174/138920212803759749] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2012] [Revised: 08/28/2012] [Accepted: 08/31/2012] [Indexed: 12/24/2022] Open
Abstract
T-lymphocytes play a central role in the effector and regulatory mechanisms of the adaptive immune response. Upon exiting the thymus they begin to undergo a series of phenotypic and functional changes that continue throughout the lifetime and being most pronounced in the elderly. The reason postulated for this is that the dynamic processes of repeated interaction with cognate antigens lead to multiple division cycles involving a high degree of cell differentiation, senescence, restriction of the T-cell receptor (TCR) repertoire, and cell cycle arrest. This cell cycle arrest is associated with the loss of telomere sequences from the ends of chromosomes. Telomere length is reduced at each cell cycle, and critically short telomeres recruit components of the DNA repair machinery and trigger replicative senescence or apoptosis. Repetitively stimulated T-cells become refractory to telomerase induction, suffer telomere erosion and enter replicative senescence. The latter is characterized by the accumulation of highly differentiated T-cells with new acquired functional capabilities, which can be caused by aberrant expression of genes normally suppressed by epigenetic mechanisms in CD4+ or CD8+ T-cells. Age-dependent demethylation and overexpression of genes normally suppressed by DNA methylation have been demonstrated in senescent subsets of T-lymphocytes. Thus, T-cells, principally CD4+CD28null T-cells, aberrantly express genes, including those of the KIR gene family and cytotoxic proteins such as perforin, and overexpress CD70, IFN-γ, LFA-1 and others. In summary, owing to a lifetime of exposure to and proliferation against a variety of pathogens, highly differentiated T-cells suffer molecular modifications that alter their cellular homeostasis mechanisms.
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25
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Broux B, Markovic-Plese S, Stinissen P, Hellings N. Pathogenic features of CD4+CD28- T cells in immune disorders. Trends Mol Med 2012; 18:446-53. [PMID: 22784556 DOI: 10.1016/j.molmed.2012.06.003] [Citation(s) in RCA: 80] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2012] [Revised: 06/06/2012] [Accepted: 06/11/2012] [Indexed: 12/20/2022]
Abstract
Aging of the immune system contributes to the increased morbidity and mortality of the elderly population and may occur prematurely in patients with immune disorders. One of the main characteristics of immunosenescence is the expansion of CD4(+)CD28(-) T cells in the blood. These cells are effector memory T cells with cytotoxic capacity, and have been recently described to have pathogenic potential in a variety of immune disorders. Interestingly, CD4(+)CD28(-) T cells have now been found to infiltrate target tissues of patients with multiple sclerosis, rheumatoid arthritis, myopathies, acute coronary syndromes, and other immune-related diseases. In this review, we discuss potential factors and mechanisms that may induce the expansion of these cells, as well as their putative pathogenic mechanisms in immune disorders.
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Affiliation(s)
- Bieke Broux
- Hasselt University, Biomedical Research Institute and Transnationale Universiteit Limburg, School of Life Sciences, 3590 Diepenbeek, Belgium
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26
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Tyagi AM, Srivastava K, Kureel J, Kumar A, Raghuvanshi A, Yadav D, Maurya R, Goel A, Singh D. Premature T cell senescence in Ovx mice is inhibited by repletion of estrogen and medicarpin: a possible mechanism for alleviating bone loss. Osteoporos Int 2012; 23:1151-61. [PMID: 21562872 DOI: 10.1007/s00198-011-1650-x] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2011] [Accepted: 03/10/2011] [Indexed: 01/01/2023]
Abstract
UNLABELLED Presently the relationship between CD28, biological marker of senescence, and ovariectomy is not well understood. We show that ovariectomy leads to CD28 loss on T cells and estrogen (E2) repletion and medicarpin (Med) inhibits this effect. We thus propose that Med/E2 prevents bone loss by delaying premature T cell senescence. INTRODUCTION Estrogen deficiency triggers reproductive aging by accelerating the amplification of TNF-α-producing T cells, thereby leading to bone loss. To date, no study has been carried out to explain the relationship between CD4(+)CD28null T cells and ovariectomy or osteoporosis. We aim to determine the effect of Ovx on CD28 expression on T cells and effects of E2 and medicarpin (a pterocarpan phytoalexin) with proven osteoprotective effect on altered T cell responses. METHODS Adult, female Balb/c mice were taken for the study. The groups were: sham, Ovx, Ovx + Med or E2. Treatments were given daily by oral gavage. At autopsy bone marrow and spleen were flushed out and cells labelled with antibodies for FACS analysis. Serum was collected for ELISA. RESULTS In Ovx mice, Med/E2 at their respective osteoprotective doses resulted in thymus involution and lowered Ovx-induced increase in serum TNF-α level and its mRNA levels in the BM T cells. Med/E2 reduced BM and spleen CD4(+) T cell proliferation and prevented CD28 loss on CD4(+) T cells. Further, Med abrogated TNF-α-induced loss of CD28 expression in the BM T cells. CONCLUSIONS To our knowledge this is the first report to determine the mechanism of CD28 loss on T cells as a result of ovariectomy. Our study demonstrates that Ovx leads to the generation of premature senescent CD4(+)CD28null T cells, an effect inhibited by E2 and Med. We propose that one of the mechanisms by which Med/E2 alleviates Ovx-induced bone loss is by delaying T cell senescence and enhancing CD28 expression.
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Affiliation(s)
- A M Tyagi
- Division of Endocrinology, Central Drug Research Institute, Council of Scientific and Industrial Research, Chattar Manzil, PO Box 173, Lucknow, India
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Sakaguchi S, Benham H, Cope AP, Thomas R. T‐cell receptor signaling and the pathogenesis of autoimmune arthritis: insights from mouse and man. Immunol Cell Biol 2012; 90:277-87. [DOI: 10.1038/icb.2012.4] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Shimon Sakaguchi
- Laboratory of Experimental Immunology, WPI Immunology Frontier Research Center, Osaka University Suita Japan
- Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University Kyoto Japan
| | - Helen Benham
- The University of Queensland, Diamantina Institute, Princess Alexandra Hospital Brisbane Queensland Australia
| | - Andrew P Cope
- Academic Department of Rheumatology, Centre for Molecular and Cellular Biology of Inflammation, Division of Immunology, Infection and Inflammatory Diseases, School of Medicine, King's College London London UK
| | - Ranjeny Thomas
- The University of Queensland, Diamantina Institute, Princess Alexandra Hospital Brisbane Queensland Australia
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Ponchel F, Vital E, Kingsbury SR, El-Sherbiny YM. CD4+T-cell subsets in rheumatoid arthritis. ACTA ACUST UNITED AC 2012. [DOI: 10.2217/ijr.11.69] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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Onyema OO, Njemini R, Bautmans I, Renmans W, De Waele M, Mets T. Cellular aging and senescence characteristics of human T-lymphocytes. Biogerontology 2011; 13:169-81. [PMID: 22102004 DOI: 10.1007/s10522-011-9366-z] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2011] [Accepted: 11/03/2011] [Indexed: 02/06/2023]
Abstract
CD28-, CD57+ and KLRG1+ are cell surface markers that have been used to describe senescent T-lymphocytes in humans. However, the relationship among these phenotypes during aging, and their relationship with the concept of in vitro cellular aging have not been well established. Using five-colour flow cytometry, we analyzed peripheral blood T-lymphocytes for their expression of CD28, CD57 and KLRG1 in 11 young (Y) and 11 old (O) apparently healthy human subjects. The proportions of CD28- and CD57+ cells were significantly higher among the T-cell populations of O compared to Y subjects; the proportion of KLRG1+ cells was significantly higher only among CD8+ cells. Populations that were more frequent in the elderly participants were characterised as CD28+ CD57+, CD28- CD57+ or CD28- CD57-. The expression of p16 and p21, considered as markers for in vitro senescence, was higher in CD28+ CD57+ cells than in other subpopulations in both age groups. The expression of p21 was age-related, which was not the case for p16. Thus, although both p16 and p21 are involved in T-cell senescence, they appear to behave differently. CMV infection and shifts in subpopulations are unlikely as explanations of the observed differences. Their higher levels of p16 and p21 expression, coupled with their higher prevalence in the elderly participants make CD28+ CD57+ cells the subpopulation of T-cells most closely corresponding to the concept of senescent cells.
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Affiliation(s)
- Oscar Okwudiri Onyema
- Gerontology Department, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Belgium
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Larbi A, Pawelec G, Wong SC, Goldeck D, Tai JJY, Fulop T. Impact of age on T cell signaling: a general defect or specific alterations? Ageing Res Rev 2011; 10:370-8. [PMID: 20933612 DOI: 10.1016/j.arr.2010.09.008] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2010] [Revised: 09/22/2010] [Accepted: 09/24/2010] [Indexed: 01/09/2023]
Abstract
Decreased immune responsiveness associated with aging is generally termed "immunosenescence". Several theories have been proposed to explain age-related declines in immune responses. Here, we will focus on and describe potential defects in T cell signal transduction from the membrane to the nucleus, leading to changes in the type, intensity and duration of the response as a major factor contributing to immunosenescence. We will first detail T cell signaling through the T cell receptor (TCR), CD28 and IL-2 receptor (IL-2R) and then discuss the observed age-related alterations to these signaling pathways. The role of membrane rafts in T cell signaling and T cell aging will be described. These factors will be considered in the context of the notion that age-related changes to T cell signaling may be attributed to changes in the functionality of the T cells due to shifts in T cell subpopulations with age. For this reason, we conclude by highlighting the application of multiparametric signaling analysis in leukocyte subsets using flow cytometry as a means to obtain a clearer picture with respect to age-related changes to immune signaling.
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Vallejo AN, Mueller RG, Hamel DL, Way A, Dvergsten JA, Griffin P, Newman AB. Expansions of NK-like αβT cells with chronologic aging: novel lymphocyte effectors that compensate for functional deficits of conventional NK cells and T cells. Ageing Res Rev 2011; 10:354-61. [PMID: 20932941 DOI: 10.1016/j.arr.2010.09.006] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2010] [Revised: 09/20/2010] [Accepted: 09/22/2010] [Indexed: 01/01/2023]
Abstract
As the repertoire of αβT cell receptors (TCR) contracts with advancing age, there is an associated age-dependent accumulation of oligoclonal T cells expressing of a variety of receptors (NKR), normally expressed on natural killer (NK) cells. Evidences for differential regulation of expression of particular NKRs between T cells and NK cells suggest that NKR expression on T cells is physiologically programmed rather than a random event of the aging process. Experimental studies show NKRs on aged αβT cells may function either as independent receptors, and/or as costimulatory receptors to the TCR. Considering the reported deficits of conventional αβTCR-driven activation and also functional deficits of classical NK cells, NKR(+) αβT cells likely represent novel immune effectors that are capable of combining innate and adaptive functions. Inasmuch as immunity is a determinant of individual fitness, the type and density of NKRs could be important contributing factors to the wide heterogeneity of health characteristics of older adults, ranging from institutionalized frail elders who are unable to mount immune responses to functionally independent community-dwelling elders who exhibit protective immunity. Understanding the biology of NKR(+) αβT cells could lead to new avenues for age-specific intervention to improve protective immunity.
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Tyagi AM, Srivastava K, Sharan K, Yadav D, Maurya R, Singh D. Daidzein prevents the increase in CD4+CD28null T cells and B lymphopoesis in ovariectomized mice: a key mechanism for anti-osteoclastogenic effect. PLoS One 2011; 6:e21216. [PMID: 21731677 PMCID: PMC3120851 DOI: 10.1371/journal.pone.0021216] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2011] [Accepted: 05/23/2011] [Indexed: 01/01/2023] Open
Abstract
Estrogen deficiency leads to an upregulation of TNF-α producing T cells and B-lymphopoesis which augments osteoclastogenesis. Estrogen deficiency also increases the population of premature senescent CD4⁺ CD28null T cells which secrete a higher amount of TNF-α thus leading to enhanced osteoclastogenesis. Isoflavonoids like daidzein and genistein are found mostly in soybeans, legumes, and peas. These share structural similarity with 17β-stradiol (E2) and have osteoprotective role. This study explores the effect of daidzein (Daid) on the proliferation of TNF-α producing T cells, premature senescent T cells and B cell lymphopoesis under estrogen deficient conditions. For this study adult Balb/c mice were treated with Daid at 10 mg/kg body weight dose by oral gavage daily post ovariectomy (Ovx). After six weeks animals were autopsied and bone marrow and spleen cells were collected for FACS analysis. Blood serum was collected for ELISA. It was observed that Ovx mice treated with Daid for six weeks show reduction in Ovx induced expansion of CD4⁺ T cells in bone marrow and spleen when analysed by flow cytometry. Estrogen deficiency led to increased prevalence of TNF-α secreting CD4⁺CD28null T cells, however, treatment with Daid increased the percentage of CD4⁺CD28⁺ T cells. Co-culture of CD4⁺CD28null T cells and bone marrow resulted in enhanced osteoclastogenesis as evident by increased tartarate resistant acid phosphatase (TRAP) expression, an osteoclast marker. However, treatment with Daid resulted in reduced osteoclastogenesis in CD4⁺CD28null T cells and bone marrow cell co-culture. Daid also regulated B lymphopoesis and decreased mRNA levels of RANKL in B220⁺ cells. Taken together, we propose that one of the mechanisms by which Daid prevents bone loss is by reversing the detrimental immune changes as a result of estrogen deficiency.
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Affiliation(s)
- Abdul Malik Tyagi
- Division of Endocrinology, Central Drug Research Institute (Council of Scientific and Industrial Research), Chattar Manzil, Lucknow, India
| | - Kamini Srivastava
- Division of Endocrinology, Central Drug Research Institute (Council of Scientific and Industrial Research), Chattar Manzil, Lucknow, India
| | - Kunal Sharan
- Division of Endocrinology, Central Drug Research Institute (Council of Scientific and Industrial Research), Chattar Manzil, Lucknow, India
| | - Dinesh Yadav
- Division of Medicinal and Process Chemistry, Central Drug Research Institute (Council of Scientific and Industrial Research), Chattar Manzil, Lucknow, India
| | - Rakesh Maurya
- Division of Medicinal and Process Chemistry, Central Drug Research Institute (Council of Scientific and Industrial Research), Chattar Manzil, Lucknow, India
| | - Divya Singh
- Division of Endocrinology, Central Drug Research Institute (Council of Scientific and Industrial Research), Chattar Manzil, Lucknow, India
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Soroczyńska-Cybula M, Bryl E, Smoleńska Z, Witkowski JM. Varying expression of four genes sharing a common regulatory sequence may differentiate rheumatoid arthritis from ageing effects on the CD4(+) lymphocytes. Immunology 2010; 132:78-86. [PMID: 20738421 DOI: 10.1111/j.1365-2567.2010.03341.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
The CD28 gene is similarly down-regulated in CD4(+) lymphocytes from both healthy elderly people and patients with rheumatoid arthritis (RA) because of impaired protein-binding activity of the 'α' sequence in its promoter region. Other genes important for the CD4(+) cell function may share that sequence and may be similarly regulated and affected. We searched GenBank for possible 'α' homologues and then compared transcriptional activities of the respective genes in the CD4(+) cells of young and older healthy individuals and those with RA by real-time PCR. We show here that genes encoding one of the zinc finger proteins (ZNF334), the 'aging hormone' Klotho, the retinoid acid receptor β2 (RARβ2) and the T-cell adapter protein GRAP-2, contain sequences with various (exceeding 70%) degrees of homology to the 'α' sequence near their promoters. These genes are transcribed in human CD4(+) lymphocytes; the expressions of RARβ2, KLOTHO and ZNF334 are significantly decreased in a correlated manner in the cells of patients with RA compared with those of healthy individuals. In RA patients, the extremely reduced expression of ZNF334 does not depend on the individual's age, apparently constituting a disease-related phenomenon; whereas that of RARβ2 and KLOTHO occurs mostly in the cells of relatively younger patients, making them similar to the lymphocytes of healthy elderly in this aspect.
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34
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Crowson CS, Liang KP, Therneau TM, Kremers HM, Gabriel SE. Could accelerated aging explain the excess mortality in patients with seropositive rheumatoid arthritis? ACTA ACUST UNITED AC 2010; 62:378-82. [PMID: 20112366 DOI: 10.1002/art.27194] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
OBJECTIVE To determine whether the mortality pattern in patients with seropositive rheumatoid arthritis (RA) is consistent with the concept of accelerated aging, by comparing the observed mortality rates in patients with RA with the age-accelerated mortality rates from the general population. METHODS A population-based inception cohort of patients with seropositive RA (according to the American College of Rheumatology 1987 criteria) was assembled and followed up for vital status until July 1, 2008. The expected mortality rate was obtained by applying the death rates from the general population to the age, sex, and calendar year distribution of the RA population. The observed mortality was estimated using Kaplan-Meier methods. Acceleration factors for the expected mortality were estimated in accelerated failure time models. RESULTS A total of 755 patients with seropositive RA (mean age 55.6 years, 69% women) were followed up for a mean of 12.5 years, during which 315 patients died. The expected median survival was age 82.4 years, whereas the median survival of the RA patients was age 76.7 years. Results of statistical modeling suggested that, in terms of mortality rates, patients with RA were effectively 2 years older than actual age at RA incidence, and thereafter the patients underwent 11.4 effective years of aging for each 10 years of calendar time. CONCLUSION The overall observed mortality experience of patients with seropositive RA is consistent with the hypothesis of accelerated aging. The causes of accelerated aging in RA deserve further investigation.
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Reactive oxygen intermediate-induced pathomechanisms contribute to immunosenescence, chronic inflammation and autoimmunity. Mech Ageing Dev 2009; 130:564-87. [PMID: 19632262 DOI: 10.1016/j.mad.2009.07.003] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2008] [Revised: 06/07/2009] [Accepted: 07/15/2009] [Indexed: 02/07/2023]
Abstract
Deregulation of reactive oxygen intermediates (ROI) resulting in either too high or too low concentrations are commonly recognized to be at least in part responsible for many changes associated with aging. This article reviews ROI-dependent mechanisms critically contributing to the decline of immune function during physiologic - or premature - aging. While ROI serve important effector functions in cellular metabolism, signalling and host defence, their fine-tuned generation declines over time, and ROI-mediated damage to several cellular components and/or signalling deviations become increasingly prevalent. Although distinct ROI-associated pathomechanisms contribute to immunosenescence of the innate and adaptive immune system, mutual amplification of dysfunctions may often result in hyporesponsiveness and immunodeficiency, or in chronic inflammation with hyperresponsiveness/deregulation, or both. In this context, we point out how imbalanced ROI contribute ambiguously to driving immunosenescence, chronic inflammation and autoimmunity. Although ROI may offer a distinct potential for therapeutic targeting along with the charming opportunity to rescue from deleterious processes of aging and chronic inflammatory diseases, such modifications, owing to the complexity of metabolic interactions, may carry a marked risk of unforeseen side effects.
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36
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Weng NP, Akbar AN, Goronzy J. CD28(-) T cells: their role in the age-associated decline of immune function. Trends Immunol 2009; 30:306-12. [PMID: 19540809 DOI: 10.1016/j.it.2009.03.013] [Citation(s) in RCA: 470] [Impact Index Per Article: 29.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2009] [Revised: 03/23/2009] [Accepted: 03/23/2009] [Indexed: 02/06/2023]
Abstract
The accumulation of CD28(-) T cells, particularly within the CD8 subset, is one of the most prominent changes during T-cell homeostasis and function associated with aging in humans. CD28, a major co-stimulatory receptor, is responsible for the optimal antigen-mediated T-cell activation, proliferation and survival of T cells. CD28(-) T cells exhibit reduced antigen receptor diversity, defective antigen-induced proliferation and a shorter replicative lifespan while showing enhanced cytotoxicity and regulatory functions. Gene expression analyses reveal profound changes of CD28(-) T cells in comparison to their CD28(+) counterparts and corroborate their functional differences. Here we review recent advances in our understanding of CD28(-) T cells and their role in the age-associated decline of immune function.
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Affiliation(s)
- Nan-Ping Weng
- Laboratory of Immunology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
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37
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Hoff H, Knieke K, Cabail Z, Hirseland H, Vratsanos G, Burmester GR, Jorch G, Nadler SG, Bröker B, Hebel K, Brunner-Weinzierl MC. Surface CD152 (CTLA-4) Expression and Signaling Dictates Longevity of CD28null T Cells. THE JOURNAL OF IMMUNOLOGY 2009; 182:5342-51. [DOI: 10.4049/jimmunol.0801624] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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Habib-Agahi M, Jaberipour M, Searle PF. 4-1BBL costimulation retrieves CD28 expression in activated T cells. Cell Immunol 2009; 256:39-46. [PMID: 19217084 DOI: 10.1016/j.cellimm.2009.01.003] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2008] [Revised: 01/06/2009] [Accepted: 01/13/2009] [Indexed: 11/28/2022]
Abstract
Binding of CD80/86 to CD28 is regarded as the main T cell costimulatory interaction. However, CD28 downregulates soon after T cell activation. To investigate potential cross-interaction between CD137 (4-1BB) and CD28, we stimulated T cells with anti-CD3 in the presence of A549 lung carcinoma cells expressing CD80/CD86 and 4-1BBL molecules, transduced into the cells using recombinant non-replicating adenoviruses. Following initial T cell proliferation, the proportion of CD28(+) cells in both CD4(+) and CD8(+) populations was rapidly reduced by CD80/86 costimulation, whereas cultures costimulated with just 4-1BBL continued to express CD28. CD28 was also downregulated in cultures costimulated with both CD80/86 and 4-1BBL. Interestingly, in cells costimulated with CD80/86 that had downregulated CD28 expression and ceased to proliferate, reactivation of proliferation by 4-1BBL costimulation also restored their CD28 expression. These findings show a positive effect of CD137 signalling on CD28 expression, similar to the effect of CD28 engagement on 4-1BB expression during the initial phases of T cell activation. Moreover, they point to the importance of signals through 4-1BB for the purposes of ex-vivo T cell activation and expansion.
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Lemster BH, Michel JJ, Montag DT, Paat JJ, Studenski SA, Newman AB, Vallejo AN. Induction of CD56 and TCR-independent activation of T cells with aging. THE JOURNAL OF IMMUNOLOGY 2008; 180:1979-90. [PMID: 18209097 DOI: 10.4049/jimmunol.180.3.1979] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Degeneration of the thymus and severe contraction of the T cell repertoire with aging suggest that immune homeostasis in old age could be mediated by distinct effectors. Therefore, receptors expressed on T cells as they undergo senescence in vitro, as well as those displayed by circulating T cells during normal chronologic aging, were examined. Monitoring of T cells driven to senescence showed de novo induction of CD56, the prototypic receptor of NK cells. Analysis of fresh T cells in peripheral blood showed an age-dependent induction of CD56. These unusual T cells expressed high levels of Bcl2, p16, and p53, and had limited, or completely lost, ability to undergo cell division, properties consistent with senescence. CD56 cross-linking without TCR ligation on CD56(+) T cells resulted in extensive protein phosphorylation, NF-kappaB activation, and Bax down-regulation. CD56 cross-linking was also sufficient to drive production of various humoral factors. These data suggest that the immunologic environment in old age is functionally distinct, rather than being a dysfunctional version of that seen at a young age. CD56(+) T cells are unique effectors capable of mediating TCR-independent immune cascades that could be harnessed to enhance protective immunity in the elderly.
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Affiliation(s)
- Bonnie H Lemster
- Department of Pediatrics, University of Pittsburgh, PA 15213, USA
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40
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Czesnikiewicz-Guzik M, Lee WW, Cui D, Hiruma Y, Lamar DL, Yang ZZ, Ouslander JG, Weyand CM, Goronzy JJ. T cell subset-specific susceptibility to aging. Clin Immunol 2008; 127:107-18. [PMID: 18222733 DOI: 10.1016/j.clim.2007.12.002] [Citation(s) in RCA: 339] [Impact Index Per Article: 19.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2007] [Revised: 12/03/2007] [Accepted: 12/07/2007] [Indexed: 12/11/2022]
Abstract
With increasing age, the competence of the immune system to fight infections and tumors declines. Age-dependent changes have been mostly described for human CD8 T cells, raising the question of whether the response patterns for CD4 T cells are different. Gene expression arrays of memory CD4 T cells yielded a similar age-induced fingerprint as has been described for CD8 T cells. In cross-sectional studies, the phenotypic changes were not qualitatively different for CD4 and CD8 T cells, but occurred much more frequently in CD8 T cells. Homeostatic stability partially explained this lesser age sensitivity of CD4 T cells. With aging, naïve and central memory CD8 T cells were lost at the expense of phenotypically distinct CD8 effector T cells, while effector CD4 T cells did not accumulate. However, phenotypic shifts on central memory T cells were also more pronounced in CD8 T cells. This distinct stability in cell surface marker expression can be reproduced in vitro. The data show that CD8 T cells are age sensitive by at least two partially independent mechanisms: fragile homeostatic control and gene expression instability in a large set of regulatory cell surface molecules.
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Affiliation(s)
- Marta Czesnikiewicz-Guzik
- Kathleen B. and Mason I. Lowance Center for Human Immunology, Emory University School of Medicine, Atlanta, GA30322, USA
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Witkowski JM, Soroczyńska-Cybula M, Bryl E, Smoleńska Z, Jóźwik A. Klotho--a common link in physiological and rheumatoid arthritis-related aging of human CD4+ lymphocytes. THE JOURNAL OF IMMUNOLOGY 2007; 178:771-7. [PMID: 17202338 DOI: 10.4049/jimmunol.178.2.771] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Human CD4(+) T lymphocytes undergo aging-related changes leading to decreased immunity to infections and neoplasms, and to increased frequency of autoimmune diseases including rheumatoid arthritis (RA). Certain changes, observed in the CD4(+) cells of RA patients, resemble those observed during physiological aging, but occur at earlier age. Underlying cellular mechanism(s) of these similarities are so far largely unknown. Here we show that KLOTHO, a beta-glucuronidase gene whose activity changes are associated with aging phenotype, is down-regulated at the mRNA, protein, and enzymatic (beta-glucuronidase) activity levels both in the healthy elderly and especially in RA CD4(+) lymphocytes. Although the exact role of Klotho activity for CD4(+) cell function is unknown, we propose here that it might be involved in anti-inflammatory processes occurring in the young and healthy individuals, but reduced in both healthy elderly and RA patients. To support this hypothesis, we show here that the reduction of Klotho expression and activity in both elderly and patients' lymphocytes occurs in concert with the down-regulation of T cell costimulatory molecule CD28, the latter known to be dependent on increased levels of TNF-alpha. Thus, a common mechanism of KLOTHO down-regulation, but executed at various times in life, may underlie both physiological and disease-related T cell aging. Klotho activity might become a target of anti-RA drug development as well as a tool to help increase the immune system efficiency in the elderly.
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Affiliation(s)
- Jacek M Witkowski
- Department of Pathophysiology, Medical University of Gdańsk, Debinki 7, 80-211 Gdańsk, Poland.
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Vallejo AN. Immune remodeling: lessons from repertoire alterations during chronological aging and in immune-mediated disease. Trends Mol Med 2007; 13:94-102. [PMID: 17267287 DOI: 10.1016/j.molmed.2007.01.005] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2006] [Revised: 01/08/2007] [Accepted: 01/19/2007] [Indexed: 01/01/2023]
Abstract
Immunological studies of aging and of patients with chronic immune-mediated diseases document overlap of immune phenotypes. Here, the term "immune remodeling" refers to these phenotypes that are indicative of biological processes of deterioration and repair. This concept is explored through lessons from studies about the changes in the T-cell repertoire and the functional diversity of otherwise oligoclonal, senescent T cells. Immune remodeling suggests a gradual process that occurs throughout life. However, similar but more drastic remodeling occurs disproportionately among young patients with chronic disease. In this article, I propose that immune remodeling is a beneficial adaptation of aging to promote healthy survival beyond reproductive performance, but acute remodeling poses risk of premature exhaustion of the immune repertoire and, thus, is detrimental in young individuals.
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Affiliation(s)
- Abbe N Vallejo
- Departments of Pediatrics and Immunology, University of Pittsburgh School of Medicine, 3460 Fifth Avenue, Pittsburgh, PA 15213, USA.
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43
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Kovaiou RD, Grubeck-Loebenstein B. Age-associated changes within CD4+ T cells. Immunol Lett 2006; 107:8-14. [PMID: 16949678 DOI: 10.1016/j.imlet.2006.07.006] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2006] [Revised: 07/21/2006] [Accepted: 07/21/2006] [Indexed: 11/16/2022]
Abstract
As individuals age their ability to respond and clear pathogens declines, leading to a greater incidence and severity of infectious diseases. Additionally, the efficacy of vaccines is frequently decreased in elderly persons. Increased susceptibility to infections and reduced protection after vaccination reflect the impact of age-related changes on the immune system. The immune system undergoes a wide range of changes with increasing age. The aim of this review is to summarize cellular and molecular aspects of aging CD4(+) T cells. CD4(+) T cells play an essential role in mediating both humoral and cellular immune responses. Therefore, age-associated dysfunctions within CD4(+) T cells have a strong clinical impact. Improving our understanding of the aged CD4(+) T cells, in particular but also of the aged immune system in general, is crucial for developing effective prevention and treatment programs which will facilitate healthy aging and improve the quality of life of the elderly population.
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Affiliation(s)
- Rania D Kovaiou
- Institute for Biomedical Aging Research, Austrian Academy of Sciences, Rennweg 10, A-6020 Innsbruck, Austria
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44
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Abedin S, Michel JJ, Lemster B, Vallejo AN. Diversity of NKR expression in aging T cells and in T cells of the aged: the new frontier into the exploration of protective immunity in the elderly. Exp Gerontol 2006; 40:537-48. [PMID: 16002251 DOI: 10.1016/j.exger.2005.04.012] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2005] [Revised: 04/26/2005] [Accepted: 04/26/2005] [Indexed: 01/10/2023]
Abstract
Aging in the immune system is characterized by the contraction of the lymphocyte repertoire, exemplified by long-lived oligoclonal T cells that pervade the peripheral circulation. T-cell receptor (TCR) repertoire contraction likely explains the decline in immunity with chronological age as evidenced by the increased morbidity and mortality to common and new infections, and the low rates of protective responses to vaccination in the elderly. Interestingly, in vitro senescence models and cross sectional ex vivo studies have consistently demonstrated that senescent (or pre-senescent) T cells and T cells of the aged express unusually high densities of receptors that are normally found on natural killer (NK) cells, the killer cell immunoglobulin-like receptors (KIR) being the most diverse NK receptors (NKR). Molecular studies also show that T cells are programmed to express NKRs/KIRs, and T-cell clonal lineages express a variety of NKRs towards the end stages of their replicative lifespan. We propose that NKR/KIR induction in aging T cells is an adaptational diversification of the immune repertoire. We suggest that NKR/KIR expression in oligoclonal senescent and pre-senescent T cells is a compensatory adaptation to maintain immune competence despite the overall contraction in TCR diversity with aging. NKRs comprise a diverse superfamily of receptors. Mounting evidence for NKR/KIR signaling pathways in T cells divergent from those seen in NK cells indicate that senescent NKR(+)T cells are unique immune effectors. We suggest that appreciation of the functional diversity of these unusual NK-like T cells is central to the creative development of new strategies to enhance protective immunity in the aged.
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Affiliation(s)
- Sameem Abedin
- Division of Rheumatology, Children's Hospital of Pittsburgh, PA 15213, USA
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45
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Sato K, Niessner A, Kopecky SL, Frye RL, Goronzy JJ, Weyand CM. TRAIL-expressing T cells induce apoptosis of vascular smooth muscle cells in the atherosclerotic plaque. ACTA ACUST UNITED AC 2006; 203:239-50. [PMID: 16418392 PMCID: PMC2118078 DOI: 10.1084/jem.20051062] [Citation(s) in RCA: 142] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Acute coronary syndromes (ACS) are precipitated by a rupture of the atherosclerotic plaque, often at the site of T cell and macrophage infiltration. Here, we show that plaque-infiltrating CD4 T cells effectively kill vascular smooth muscle cells (VSMC). VSMCs sensitive to T cell-mediated killing express the death receptor DR5 (TNF-related apoptosis-inducing ligand [TRAIL] receptor 2), and anti-TRAIL and anti-DR5 antibodies block T cell-mediated apoptosis. CD4 T cells that express TRAIL upon stimulation are expanded in patients with ACS and more effectively induce VSMC apoptosis. Adoptive transfer of plaque-derived CD4 T cells into immunodeficient mice that are engrafted with human atherosclerotic plaque results in apoptosis of VSMCs, which was prevented by coadministration of anti-TRAIL antibody. These data identify that the death pathway is triggered by TRAIL-producing CD4 T cells as a direct mechanism of VSMC apoptosis, a process which may lead to plaque destabilization.
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Affiliation(s)
- Kayoko Sato
- Department of Medicine, Kathleen B. and Mason I. Lowance Center for Human Immunology, Emory School of Medicine, Atlanta, GA 30322, USA
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Jurivich DA, Choo M, Welk J, Qiu L, Han K, Zhou X. Human aging alters the first phase of the molecular response to stress in T-cells. Exp Gerontol 2005; 40:948-58. [PMID: 16168601 DOI: 10.1016/j.exger.2005.08.003] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2005] [Revised: 08/01/2005] [Accepted: 08/05/2005] [Indexed: 10/25/2022]
Abstract
This study examines how age affects the first phase of the heat shock response in human T-cells. To understand how age alters transcriptional regulation of the heat shock genes, a cross-sectional study was conducted utilizing human T-cells enriched from peripheral blood lymphocytes of healthy young (20-40 years old) and old (>70 years old) donors. Nuclear run-on analysis revealed a 66% reduction in hsp70 transcription rates in old compared to young nuclei harvested from T-cells exposed to a brief 42 degrees C heat shock. To determine if one or more protein transactivators of the proximal and distal promoter regions of the hsp70 gene were affected by age, gel shift analysis was performed. Both HSF1 and SP1 DNA-binding were reduced with age but no reduction was noted in CCAAT-DNA binding. Western blot analysis indicated that HSF1 but not HSF2 protein levels were reduced in aged donor samples. These data suggest that human T-cell senescence involves a multi-factorial mechanism that diminishes an important transcriptional response to thermal stress. The results are discussed relative to recent studies that support a multi-factorial mechanism for age-dependent attenuation of the heat shock transcription factor.
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Affiliation(s)
- Donald A Jurivich
- Department of Medicine, Section of Geriatric Medicine (m/c 717), University of Illinois at Chicago & Jesse Brown VA Medical Center, 840 S. Wood St Chicago, IL 60612, USA.
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Nikolich-Zugich J, Messaoudi I. Mice and flies and monkeys too: caloric restriction rejuvenates the aging immune system of non-human primates. Exp Gerontol 2005; 40:884-93. [PMID: 16087306 DOI: 10.1016/j.exger.2005.06.007] [Citation(s) in RCA: 91] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2005] [Revised: 06/28/2005] [Accepted: 06/28/2005] [Indexed: 11/21/2022]
Abstract
Humanity has been obsessed with extending life span and reversing the aging process throughout recorded history and this quest most likely preceded the invention of the written word. The search for eternal youth has spurred holy wars and precipitated the discovery of the new world (the 'Fountain of youth'). It therefore comes as no surprise that an increasingly greater amount of research effort is dedicated to improve our understanding of the aging process and finding interventions to moderate its impact on health. Caloric restriction (CR) is the only intervention in biology that consistently extends maximal and median life span in a variety of short-lived species. Several theories to explain the mechanisms of action of CR have been put forth, including the possibility that CR acts by retarding immune senescence. The question remains, however, whether CR will have the same beneficial impact on human aging, and, if so, how long does CR need to last to produce beneficial effects. To address this question, several groups initiated long-term studies in Rhesus macaques (RM) in the 1980s. Here, we review published data describing the impact of CR on the aging immune system of mice and primates, and discuss our unpublished data that delineate similarities and differences in the effects of CR upon T cell aging and homeostasis between these two models.
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Affiliation(s)
- Janko Nikolich-Zugich
- Vaccine and Gene Therapy Institute and the Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006, USA.
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Abstract
Therapeutic efficacy of depleting B cells or blocking T-cell costimulation in rheumatoid arthritis (RA) has confirmed the critical pathogenic role of adaptive immune responses. Yet, RA preferentially affects elderly individuals, in whom adaptive immunity to exogenous antigens begins to fail. Here, we propose that senescence of the immune system is a risk factor for RA, with chronic inflammation resulting from the accumulation of degenerate T cells that have a low threshold for activation and utilize a spectrum of novel receptors to respond to microenvironmental cues. The process of immunosenescence is accelerated in RA and precedes the onset of disease, the acceleration, in part, being conferred by the HLA-DR4 haplotype. Naive CD4(+) T cells in RA are contracted in diversity and restricted in clonal burst. Senescence of effector CD4(+) T cells is associated with the loss of CD28 and the de novo expression of KIR2DS2, NKG2D, and CX(3)CR1, all of which function as costimulatory molecules and reduce the threshold for T-cell activation. The synovial microenvironment promotes chronic persistent immune responses by facilitating ectopic lymphoid neogenesis, such as the formation of aberrant germinal centers. With the propensity to develop complex lymphoid architectures and to provide optimal activation conditions for senescent CD4(+) T cells, the synovium becomes a natural target for pathogenic immune responses in prematurely aged individuals.
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Affiliation(s)
- Jörg J Goronzy
- Department of Medicine, Kathleen B. and Mason I. Lowance Center for Human Immunology, Emory School of Medicine, Atlanta, GA 30322, USA.
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Fann M, Chiu WK, Wood WH, Levine BL, Becker KG, Weng NP. Gene expression characteristics of CD28null memory phenotype CD8+ T cells and its implication in T-cell aging. Immunol Rev 2005; 205:190-206. [PMID: 15882354 DOI: 10.1111/j.0105-2896.2005.00262.x] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Accumulation of CD28(null)CD8(+) T cells is considered as one of the hallmarks of aging in the human immune system. However, the precise changes of CD28(null)CD8(+) T cells, compared to those of the precursor CD28(+)CD8(+) memory T cells, have not been determined. In this study, we present an analysis of the global gene expression profiles of CD28(+) and CD28(null) memory phenotype CD8(+) T cells. These two CD8(+) T subsets exhibited an overall similar gene expression profile with only a few dozen genes that were differentially expressed. A wide range of functions, including co-stimulation, effector activity, signaling, and transcription, were possessed by these differentially expressed genes, reflecting significant functional changes of CD28(null) memory phenotype CD8(+) T cells from their CD28(+) counterparts. In addition, CD28(null) memory CD8(+) T cells expressed several natural killer cell receptors and high levels of granzymes, perforin, and FasL, indicating an increasing capacity for cytotoxicity during memory CD8(+) T-cell aging. Interestingly, in vitro culture of these two subsets with interleukin-15 showed that similar gene expression changes occurred in both subsets. Our analysis provides the gene expression portraits of CD28(null) memory phenotype CD8(+) T cells and alteration from their CD28(+) counterparts and suggests potential mechanisms of T-cell aging.
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Affiliation(s)
- Monchou Fann
- Laboratory of Immunology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
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Vallejo AN. CD28 extinction in human T cells: altered functions and the program of T-cell senescence. Immunol Rev 2005; 205:158-69. [PMID: 15882352 DOI: 10.1111/j.0105-2896.2005.00256.x] [Citation(s) in RCA: 303] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
The loss of CD28 expression on T cells is the most consistent biological indicator of aging in the human immune system, and the frequency of CD28(null) T cells is a key predictor of immune incompetence in the elderly. There is also mounting evidence for the high frequency of these unusual T cells among patients with inflammatory syndromes or with chronic infections disproportionate with their age. In these pathological states, CD28(null) T cells likely represent prematurely senescent lymphocytes due to persistent immune activation. Unlike the situation in CD28 gene knockout mice that have anergic CD28(0/0) T cells, human CD28(null) T cells are functionally active, long-lived, oligoclonal lymphocytes that lack or have limited proliferative capacity. Results of replicative senescence studies show that CD28(null) T cells are derived from CD28(+) precursors that have undergone repeated stimulation, indicating that CD28 silencing underlies the program of T-cell aging. Dissection of the machinery regulating CD28 expression is paving the way in elucidating the molecular events leading to immune senescence as well as providing clues into the functional rejuvenation of senescent T cells.
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Affiliation(s)
- Abbe N Vallejo
- Department of Pediatrics, University of Pittsburgh School of Medicine, Division of Rheumatology, Children's Hospital of Pittsburgh, PA 15213, USA.
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