• estrogen
• menopause
• ovariectomy
• rabies virus
• vaccine
• viral neutralizing antibodies

• MOST | National Key Research and Development Program of China (NKPs)
• MOST | National Natural Science Foundation of China (NSFC)
• 山东省科学技术厅 | Natural Science Foundation of Shandong Province (山东省自然科学基金)
• Open Foundation of Shandong Key Laboratory of Oral Tissue Regeneration
• Clinical Medical Technology Innovation Project of Jinan City

• Health sciences
• Immune response
• Immunology
• Virology

• P01 AI165077 NIAID NIH HHS

• T helper type-2
• high-DHA canola oil
• infant immune system development

• Animals
• Mice
• Docosahexaenoic Acids/pharmacology
• Arachidonic Acid
• Interleukin-6
• Hypersensitivity
• Cytokines/metabolism
• Ovalbumin/pharmacology
• Immunoglobulin G
• T-Lymphocytes/metabolism
• Mice, Inbred BALB C
• Immune Tolerance

• gene therapy
• hemophilia A
• inhibitors
• platelets
• preconditioning

• Mice
• Animals
• Busulfan/metabolism
• Interferon-gamma/metabolism
• Hemophilia A
• Blood Platelets/metabolism
• Mice, Knockout
• Hemostatics
• CD8-Positive T-Lymphocytes

• R01 HL102035 NHLBI NIH HHS

• CD39
• CD4+ T-cells
• CD73
• COVID-19
• MHC class II Tetramer
• PD-1
• SARS-CoV-2
• T-cell memory
• TIGIT
• anti-CD20 therapy

• CD4-Positive T-Lymphocytes
• COVID-19
• Humans
• Phenotype
• SARS-CoV-2
• T-Lymphocytes, Helper-Inducer

• U19 AI135817 NIAID NIH HHS
• NIDDK 3U19AI135817-04S1 NIH HHS

• B cell
• TIL
• TLS
• TRM
• lung adenocarcinoma

• Adenocarcinoma of Lung/pathology
• CD8-Positive T-Lymphocytes
• Humans
• Lung Neoplasms
• Lymphocytes, Tumor-Infiltrating
• Tertiary Lymphoid Structures/pathology

• National Natural Science Foundation of China

The interplay between T- and B-cell compartments during naïve, effector and memory T cell maturation is critical for a balanced immune response. Primary B-cell immunodeficiency arising from X-linked agammaglobulinemia (XLA) offers a model to explore B cell impact on T cell subsets, starting from the thymic selection. Here we investigated characteristics of naïve and effector T cell subsets in XLA patients, revealing prominent alterations in the corresponding T-cell receptor (TCR) repertoires. We observed immunosenescence in terms of decreased diversity of naïve CD4⁺ and CD8⁺ TCR repertoires in XLA donors. The most substantial alterations were found within naïve CD4⁺ subsets, and we have investigated these in greater detail. In particular, increased clonality and convergence, along with shorter CDR3 regions, suggested narrower focused antigen-specific maturation of thymus-derived naïve T_reg (CD4⁺CD45RA⁺CD27⁺CD25⁺) in the absence of B cells - normally presenting diverse self and commensal antigens. The naïve T_reg proportion among naïve CD4 T cells was decreased in XLA patients, supporting the concept of impaired thymic naïve T_reg selection. Furthermore, the naïve T_reg subset showed prominent differences at the transcriptome level, including increased expression of genes specific for antigen-presenting and myeloid cells. Altogether, our findings suggest active B cell involvement in CD4 T cell subsets maturation, including B cell-dependent expansion of the naïve Treg TCR repertoire that enables better control of self-reactive T cells.

• CDR3β features
• T cell gene expression
• TCR repertoire
• X-linked agammaglobulinemia (XLA)
• naïve regulatory T cells

Dendritic cells are the antigen presenting cells that process antigens effectively and prime the immune system, a characteristic that have gained them the spotlights in recent years. B cell antigen presentation, although less prominent, deserves equal attention. B cells select antigen experienced CD4 T cells to become memory and initiate an orchestrated genetic program that maintains memory CD4 T cells for life of the individual. Over years of research, we have demonstrated that low levels of antigens captured by B cells during the resolution of an infection render antigen experienced CD4 T cells into a quiescent/resting state. Our studies suggest that in the absence of antigen, the resting state associated with low-energy utilization and proliferation can help memory CD4 T cells to survive nearly throughout the lifetime of mice. In this review we would discuss the primary findings from our lab as well as others that highlight our understanding of B cell antigen presentation and the contributions of the MHC Class II accessory molecules to this outcome. We propose that the quiescence induced by the low levels of antigen presentation might be a mechanism necessary to regulate long-term survival of CD4 memory T cells and to prevent cross-reactivity to autoantigens, hence autoimmunity.

• B cell Ag presentation
• CD4 lymphocyte
• gene regulation
• longevity
• memory
• new CD4 memory markers
• resting memory CD4+ T-cells

• B cell biology
• animal models: murine
• antigen presentation/recognition
• immune regulation
• immunobiology
• immunosuppression/immune modulation
• translational research/science

• alloantibody
• basic (laboratory) research/science
• immunobiology
• immunosuppression/immune modulation
• infection and infectious agents - viral: Cytomegalovirus (CMV)
• islet transplantation
• re-transplantation
• rejection: T cell-mediated (TCMR)
• tolerance

B lymphocytes are crucial mediators of systemic immune responses and are known to be substantial in the pathogenesis of autoimmune diseases with cutaneous manifestations. Amongst them are lupus erythematosus, dermatomyositis, systemic sclerosis and psoriasis, and particularly those driven by autoantibodies such as pemphigus and pemphigoid. However, the concept of autoreactive skin-associated B cells, which may reside in the skin and locally contribute to chronic inflammation, is gradually evolving. These cells are believed to differ from B cells of primary and secondary lymphoid organs and may provide additional features besides autoantibody production, including cytokine expression and crosstalk to autoreactive T cells in an antigen-presenting manner. In chronically inflamed skin, B cells may appear in tertiary lymphoid structures. Those abnormal lymph node-like structures comprise a network of immune and stromal cells possibly enriched by vascular structures and thus constitute an ideal niche for local autoimmune responses. In this review, we describe current considerations of different B cell subsets and their assumed role in skin autoimmunity. Moreover, we discuss traditional and B cell-associated approaches for the treatment of autoimmune skin diseases, including drugs targeting B cells (e.g., CD19- and CD20-antibodies), plasma cells (e.g., proteasome inhibitors, CXCR4 antagonists), activated pathways (such as BTK- and PI3K-inhibitors) and associated activator molecules (BLyS, APRIL).

• B cells
• BAFF
• BLyS
• autoantibodies
• autoimmunity
• lupus erythematosus
• pemphigoid
• pemphigus
• skin
• tertiary lymphoid structures

• CD4 T cell
• Cell longevity
• Gene
• Genetic programs
• Memory T cell
• Memory cell markers

• Adult
• Aging/genetics
• Animals
• CD4-Positive T-Lymphocytes/immunology
• CD4-Positive T-Lymphocytes/metabolism
• CD4-Positive T-Lymphocytes/physiology
• Cell Differentiation/immunology
• Cell Proliferation/genetics
• Cytokines/metabolism
• Humans
• Immunologic Memory/genetics
• Immunologic Memory/immunology
• Interferon-gamma/metabolism
• Lymphocyte Activation/genetics
• Lymphocyte Activation/immunology
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Transgenic

• R01 AI120634 NIAID NIH HHS
• Howard Hughes Medical Institute
• F30 AI136704 NIAID NIH HHS
• R01 AI063764 NIAID NIH HHS
• R21 AI101987 NIAID NIH HHS
• R01 AI121174 NIAID NIH HHS

• antigen
• bone marrow
• effector
• memory T helper cell
• niche

• antibody
• chickens
• cytokines
• in ovo
• lactobacilli

• Canadian Poultry Research Council
• Ontario Ministry of Agriculture, Food and Rural Affairs
• Natural Sciences and Engineering Research Council of Canada

CD4 T cell memory is fundamental for long-lasting immunity and effective secondary responses following infection or vaccination. We have previously found that memory CD4 T cells specific for systemic antigens preferentially reside in the bone marrow (BM) and arise from splenic CD49b⁺T-bet⁺ CD4 T cells. However, how BM-homing memory precursors are generated during an immune reaction is unknown. We show here that BM memory precursors are generated via augmented rates of cell division throughout a primary immune response. Treatment with the cytostatic drug cyclophosphamide or blockade of the CD28/B7 co-stimulatory pathway at the beginning of the contraction phase abrogates the generation of BM memory precursors. We determine that, following a critical number of cell divisions, memory precursors downregulate CCR7 and upregulate IL-2Rβ, indicating that loss of CCR7 and gain of IL-2 signal are required for the migration of memory precursors toward the BM.

• CD4 T cells
• bone marrow
• cell division
• memory
• migration

Interaction between B and CD4 T cells is crucial for their optimal responses in adaptive immunity. Immune responses augmented by their partnership promote chronic inflammation. Here we report that interaction between B and CD4 T cells augments their atherogenicity to promote lipid-induced atherosclerosis. Genetic deletion of the gene encoding immunoglobulin mu (μ) heavy chain (μMT) in ApoE^−/− mice resulted in global loss of B cells including those in atherosclerotic plaques, undetectable immunoglobulins and impaired germinal center formation. Despite unaffected numbers in the circulation and peripheral lymph nodes, CD4 T cells were also reduced in spleens as were activated and memory CD4 T cells. In hyperlipidemic μMT^−/− ApoE^−/− mice, B cell deficiency decreased atherosclerotic lesions, accompanied by absence of immunoglobulins and reduced CD4 T cell accumulation in lesions. Adoptive transfer of B cells deficient in either MHCII or co-stimulatory molecule CD40, molecules required for B and CD4 T cell interaction, into B cell-deficient μMT^−/− ApoE^−/− mice failed to increase atherosclerosis. In contrast, wildtype B cells transferred into μMT^−/− ApoE^−/− mice increased atherosclerosis and increased CD4 T cells in lesions including activated and memory CD4 T cells. Transferred B cells also increased their expression of atherogenic cytokines IL-1β, TGF-β, MCP-1, M-CSF, and MIF, with partial restoration of germinal centers and plasma immunoglobulins. Our study demonstrates that interaction between B and CD4 T cells utilizing MHCII and CD40 is essential to augment their function to increase atherosclerosis in hyperlipidemic mice. These findings suggest that targeting B cell and CD4 T cell interaction may be a therapeutic strategy to limit atherosclerosis progression.

• B cells
• CD4 T cells
• CD40
• MHCII
• atherosclerosis

• Antibody
• BLF1-C domain
• BLF1-N domain
• Burkholderia lethal factor 1 (BLF1)
• Burkholderia pseudomallei
• Protective efficacy

• Antibody-mediated rejection
• B cell immunity
• Cynomolgus monkey renal transplantation
• Donor-specific antibody
• PI3Kδ
• Rat cardiac transplantation

The role played by the humoral immune response in animals vaccinated against a mycobacterial disease such as paratuberculosis, is not well understood. Sheep vaccinated against Mycobacterium avium subsp. paratuberculosis (MAP) can still become infected and in some cases succumb to clinical disease. The strength and location of the humoral immune response following vaccination could contribute to the ability of sheep to clear MAP infection. We examined the peripheral antibody response along with the localised humoral response at the site of paratuberculosis infection, the ileum, to better understand how this contributes to MAP infection of sheep following vaccination and exposure.

Through assessing MAP specific serum IgG1 and IgG levels we show that the timing and strength of the humoral immune response directly relates to prevention of infection following vaccination. Vaccinated sheep that subsequently became infected had significantly reduced levels of MAP specific serum IgG1 early after vaccination. In contrast, vaccinated sheep that did not subsequently become infected had significantly elevated MAP specific serum IgG1 following vaccination. Furthermore, at 12 months post MAP exposure, vaccinated and subsequently uninfected sheep had downregulated expression of genes related to the humoral response in contrast to vaccinated infected sheep where expression levels were upregulated.

The timing and strength of the humoral immune response following vaccination against paratuberculosis in sheep directly relates to subsequent infection status. An initial strong IgG1 response following vaccination was crucial to prevent infection. Additionally, vaccinated uninfected sheep were able to modulate that response following apparent MAP clearance, unlike vaccinated infected animals where there was apparent dysregulation of the humoral response, which is associated with progression to clinical disease.

• Antibody
• ELISA
• Gene expression
• Humoral immunity
• Ileum
• Infection
• Paratuberculosis
• Sheep
• Vaccination

B cells have a number of different roles in the immune response. Their excellent antigen presentation potential can contribute to the activation of other cells of the immune system, and evidence is emerging that specialized subsets of these cells, that may be increased with age, can influence the cell-mediated immune system in antitumor responses. They can also regulate immune responses, to avoid autoreactivity and excessive inflammation. Deficiencies in regulatory B cells may be beneficial in cancer but will only exacerbate the inflammatory environment that is a hallmark of aging. The B cell role as antibody producers is particularly important, since antibodies perform numerous different functions in different environments. Although studying tissue responses in humans is not as easy as in mice, we do know that certain classes of antibodies are more suited to protecting the mucosal tissues (IgA) or responding to T-independent bacterial polysaccharide antigens (IgG₂) so we can make some inference with respect to tissue-specific immunity from a study of peripheral blood. We can also make inferences about changes in B cell development with age by looking at the repertoire of different B cell populations to see how age affects the selection events that would normally occur to avoid autoreactivity, or increase specificity, to antigen.

To investigate the role of glutathione S-transferase T1 donor-specific T lymphocytes in plasma cell-rich rejection of liver allografts.

The study group included 22 liver transplant patients. Among them, 18 patients were mismatched for the glutathione S-transferase T1 (GSTT1) alleles (don+/rec-), and 4 were matched (don+/rec+). Seven of the mismatched patients produced anti-GSTT1 antibodies and developed plasma cell-rich rejection (former de novo immune hepatitis). For the detection of specific T lymphocytes, peripheral blood mononuclear cells were collected and stored in liquid nitrogen. The memory T cell response was studied by adding to the cell cultures to a mix of 39 custom-made, 15-mer overlapping peptides, which covered the entire GSTT1 amino acid sequence. The specific cellular response to peptides was analyzed by flow cytometry using the markers CD8, CD4, IL-4 and IFNγ.

Activation of CD8⁺ T cells with different peptides was observed exclusively in the group of patients with plasma-cell rich rejection (3 out of 7), with production of IL-4 and/or IFNγ at a rate of 1%-4.92% depending on the peptides. The CD4⁺ response was most common and not exclusive for patients with the disease, where 5 out of 7 showed percentages of activated cells from 1.24% to 31.34%. Additionally, two patients without the disease but with the mismatch had cells that became stimulated with some peptides (1.45%-5.18%). Highly unexpected was the finding of a double positive CD4⁺CD8^low T cell population that showed the highest degree of activation with some of the peptides in 7 patients with the mismatch, in 4 patients with plasma cell-rich rejection and in 3 patients without the disease. Unfortunately, CD4⁺CD8^low cells represent 1% of the total number of lymphocytes, and stimulation could not be analyzed in 9 patients due to the low number of gated cells. Cells from the 4 patients included as controls did not show activation with any of the peptides.

Patients with GSTT1 mismatch can develop a specific T-cell response, but the potential role of this response in the pathogenesis of plasma cell-rich rejection is unknown.

• Donor-specific glutathione S-transferase T1 antibodies
• Indirect presentation
• Glutathione S-transferase T1-memory T cells
• De novo immune hepatitis
• Donor/recipient mismatch

T follicular helper cells (Tfh) provide crucial signals for germinal center (GC) formation, but Tfh populations are heterogeneous. While PD1^hi Tfh are important in the GC response, the function of the PD1^lo Tfh-like subset is unknown. We show that these cells, like the PD1^hi GC–Tfh, depend upon B cells; however, their entry to follicles is independent of CXCR5 or cognate interactions with B cells. The differentiation into PD1^hi Tfh is dependent on MHC class II interactions with B cells and requires CXCR5. Our data suggest a Tfh differentiation pathway that is initially B cell-independent, then dependent on non-cognate B cell interactions, and finally following cognate interaction with B cells and CXCR5-ligands allows the formation of GC–Tfh. The PD1^lo Tfh-like cells make early cytokine responses and may represent precursors of CD4 memory cells.

• T cell heterogeneity
• T cell memory
• T follicular helper cell subsets
• T follicular helper cells
• germinal centres

The immune responses of humans and animals to insults (i.e., infections, traumas, tumoral transformation and radiation) are based on an intricate network of cells and chemical messengers. Abnormally high inflammation immediately after insult or abnormally prolonged pro-inflammatory stimuli bringing about chronic inflammation can lead to life-threatening or severely debilitating diseases. Mesenchymal stem cell (MSC) transplant has proved to be an effective therapy in preclinical studies which evaluated a vast diversity of inflammatory conditions. MSCs lead to resolution of inflammation, preparation for regeneration and actual regeneration, and then ultimate return to normal baseline or homeostasis. However, in clinical trials of transplanted MSCs, the expectations of great medical benefit have not yet been fulfilled. As a practical alternative to MSC transplant, a synthetic drug with the capacity to boost endogenous MSC expansion and/or activation may also be effective. Regarding this, IMT504, the prototype of a major class of immunomodulatory oligonucleotides, induces in vivo expansion of MSCs, resulting in a marked improvement in preclinical models of neuropathic pain, osteoporosis, diabetes and sepsis. IMT504 is easily manufactured and has an excellent preclinical safety record. In the small number of patients studied thus far, IMT504 has been well-tolerated, even at very high dosage. Further clinical investigation is necessary to demonstrate the utility of IMT504 for resolution of inflammation and regeneration in a broad array of human diseases that would likely benefit from an immunoprotective/immunoregenerative therapy.

• Immunohomeostasis
• Immunoprotection
• Immunoregeneration
• Inflammation
• Mesenchymal stem cells
• IMT504

• antimitochondrial antibody
• primary biliary cholangitis
• ursodeoxycholic acid

The concept of immune memory forms the biological basis for vaccination programs. Despite advancements in the field of immune memory and vaccination, most current vaccines are evaluated by magnitude of antigen-specific antibody titers in serum or mucosa after vaccination. It has been shown, however, that antibody-mediated humoral immune memory is established regardless of the magnitude and duration of immune reactions, suggesting that assessment of vaccine efficacy should be performed for several years after vaccination. This long-term investigation is disadvantageous for prevalent and pandemic infections. Long-lived memory plasma cells and memory helper T cells which contribute to humoral immune memory are generated in the bone marrow after migration of memory cell precursors through bloodstream. Thus, it may be a novel evaluation strategy to assess the precursors of memory cells in the blood in the early phase of the immune reaction(s). We here review recent advances on the generation and maintenance of immune memory cells involved in humoral immunity and introduce a current concept of direct and short-term assessment of humoral immune memory formation upon vaccination as a correlate of protection.

• Adaptive immunity
• Digestive system diseases
• IL-10
• Regulatory B cells

• Antibodies
• B cells
• Clinical correlations
• Tumour models

• Animals
• Antibodies/immunology
• B-Lymphocytes/immunology
• Disease Models, Animal
• Humans
• Mice
• Neoplasms/immunology

• National Health and Medical Research Council (AU)
• Cancer Council NSW (AU)
• Cancer Institute NSW

During an immune reaction, some antigen-experienced CD4 T cells relocate from secondary lymphoid organs (SLOs) to the bone marrow (BM) in a CD49b-dependent manner and reside and rest there as professional memory CD4 T cells. However, it remains unclear how the precursors of BM memory CD4 T cells are generated in the SLOs. While several studies have so far shown that B cell depletion reduces the persistence of memory CD4 T cells in the spleen, we here show that B cell depletion enhances the establishment of memory CD4 T cells in the BM and that B cell transfer conversely suppresses it. Interestingly, the number of antigen-experienced CD4 T cells in the BM synchronizes the number of CD49b⁺T-bet⁺ antigen-experienced CD4 T cells in the spleen. CD49b⁺T-bet⁺ antigen-experienced CD4 T cells preferentially localize in the red pulp area of the spleen and the BM in a T-bet-independent manner. We suggest that B cells negatively control the generation of CD49b⁺T-bet⁺ precursors of resting memory CD4 T cells in the spleen and may play a role in bifurcation of activated effector and resting memory CD4 T cell lineages.

• B cells
• CD4 T helper cells
• T-bet
• bone marrow
• resting memory

• B cells
• T/B-cell collaboration
• antigen presentation
• co-stimulatory molecules

• B cell subtypes
• antibodies
• antigen presentation
• costimulation
• cytokines
• multiple sclerosis
• therapy

• dna-hsp65 vaccine
• memory t cells
• b cells

• Animals
• B-Lymphocytes/immunology
• B-Lymphocytes/metabolism
• Flow Cytometry
• Gene Expression/genetics
• Heat-Shock Proteins/immunology
• Heat-Shock Proteins/therapeutic use
• Immunologic Memory/physiology
• Immunomodulation/genetics
• Immunophenotyping/classification
• Inflammation Mediators/analysis
• Interferon-gamma/analysis
• Interleukin-10/genetics
• Interleukin-10/immunology
• Interleukin-12/analysis
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• RNA, Messenger/genetics
• RNA, Messenger/immunology
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction
• Spleen/cytology
• Spleen/immunology
• T-Lymphocyte Subsets/classification
• T-Lymphocyte Subsets/immunology
• Vaccines, DNA/immunology
• Vaccines, DNA/therapeutic use

• Acyltransferases/immunology
• Animals
• Antigens, Bacterial/immunology
• B-Lymphocytes/immunology
• Bacterial Proteins/immunology
• Cell Proliferation
• Cells, Cultured
• Cytokines/immunology
• Female
• Immunologic Memory/immunology
• Interferon-gamma/immunology
• Interleukins/immunology
• Lymphocyte Activation/immunology
• Mice
• Mice, Inbred C57BL
• Mycobacterium tuberculosis/immunology
• Phosphatidylinositol 3-Kinase/metabolism
• Programmed Cell Death 1 Ligand 2 Protein/immunology
• Programmed Cell Death 1 Receptor/metabolism
• Signal Transduction/immunology
• Th1 Cells/immunology
• Tuberculosis Vaccines/immunology
• Vaccination
• Vaccines, Subunit/immunology
• Interleukin-22

Immunological memory is one of the defining features of the adaptive immune system. As key orchestrators and mediators of immunity, CD4 T cells are central to the vast majority of adaptive immune responses. Generated following an immune response, memory CD4 T cells retain pertinent information about their activation environment enabling them to make rapid effector responses upon reactivation. These responses can either benefit the host by hastening the control of pathogens or cause damaging immunopathology. Here, we will discuss the diversity of the memory CD4 T cell pool, the signals that influence the transition of activated T cells into that pool, and highlight how activation requirements differ between naïve and memory CD4 T cells. A greater understanding of these factors has the potential to aid the design of more effective vaccines and to improve regulation of pathologic CD4 T cells, such as in the context of autoimmunity and allergy.

• CD4 T cell
• autoimmunity
• cytokine
• differentiation
• epigenetic
• infection
• memory
• vaccine

Current acellular pertussis vaccines have various shortcomings, which may contribute to their suboptimal efficacy and waning immunity in vaccinated populations. This calls for the development of new pertussis vaccines capable of inducing long-lived protective immunity. Immunization with whole cell pertussis vaccines and natural infection with Bordetella pertussis induce distinct and more protective immune responses when compared with immunization with acellular pertussis vaccines. Therefore, the immune responses induced with whole cell vaccine or after infection can be used as a benchmark for the development of third-generation vaccines against pertussis. Here, we review the literature on the immunology of B. pertussis infection and vaccination and discuss the lessons learned that will help in the design of improved pertussis vaccines.

To develop improved pertussis vaccines capable of inducing long-lived protective immunity, lessons have to be learned from immunology of Bordetella pertussis infection and current vaccination.

• Bordetella pertussis
• T cell
• Toll-like receptor agonist
• immunology
• vaccine

Although B cell depletion therapy (BCDT) is effective in a subset of rheumatoid arthritis (RA) patients, both mechanisms and biomarkers of response are poorly defined. Here we characterized abnormalities in B cell populations in RA and the impact of BCDT in order to elucidate B cell roles in the disease and response biomarkers. In active RA patients both CD27+IgD- switched memory (SM) and CD27-IgD- double negative memory (DN) peripheral blood B cells contained significantly higher fractions of CD95+ and CD21- activated cells compared to healthy controls. After BCD the predominant B cell populations were memory, and residual memory B cells displayed a high fraction of CD21- and CD95+ compared to pre-depletion indicating some resistance of these activated populations to anti-CD20. The residual memory populations also expressed more Ki-67 compared to pre-treatment, suggesting homeostatic proliferation in the B cell depleted state. Biomarkers of clinical response included lower CD95+ activated memory B cells at depletion time points and a higher ratio of transitional B cells to memory at reconstitution. B cell function in terms of cytokine secretion was dependent on B cell subset and changed with BCD. Thus, SM B cells produced pro-inflammatory (TNF) over regulatory (IL10) cytokines as compared to naïve/transitional. Notably, B cell TNF production decreased after BCDT and reconstitution compared to untreated RA. Our results support the hypothesis that the clinical and immunological outcome of BCDT depends on the relative balance of protective and pathogenic B cell subsets established after B cell depletion and repopulation.

• Aged
• Antirheumatic Agents/therapeutic use
• Arthritis, Rheumatoid/immunology
• Arthritis, Rheumatoid/pathology
• Arthritis, Rheumatoid/therapy
• B-Lymphocytes/drug effects
• B-Lymphocytes/immunology
• B-Lymphocytes/pathology
• Biomarkers/analysis
• Female
• Humans
• Immunoglobulin D/analysis
• Immunoglobulin D/immunology
• Interleukin-10/analysis
• Interleukin-10/immunology
• Ki-67 Antigen/analysis
• Ki-67 Antigen/immunology
• Lymphocyte Depletion/methods
• Male
• Middle Aged
• Receptors, Complement 3d/analysis
• Receptors, Complement 3d/immunology
• Rituximab/therapeutic use
• Tumor Necrosis Factor-alpha/analysis
• Tumor Necrosis Factor-alpha/immunology
• fas Receptor/analysis
• fas Receptor/immunology

• R37 AI049660 NIAID NIH HHS
• U19 AI56390 NIAID NIH HHS
• U19 AI056390 NIAID NIH HHS
• R01 AI077674 NIAID NIH HHS
• P01 AI078907 NIAID NIH HHS
• U19 AI110483 NIAID NIH HHS

• IL-10
• multiple sclerosis
• regulatory B cells
• rheumatoid arthritis
• systemic lupus erythematosus

• Animal Models
• Autoimmune Disease
• Bregs
• IL-10
• Immune Regulation

• Antibodies
• B cells
• FcγR
• Mycobacterium tuberculosis
• Tuberculosis

• Animals
• Antibodies, Bacterial/biosynthesis
• Antibodies, Bacterial/immunology
• Antigen Presentation
• B-Lymphocytes/immunology
• B-Lymphocytes/microbiology
• B-Lymphocytes/pathology
• Cytokines/biosynthesis
• Cytokines/immunology
• Granuloma/immunology
• Granuloma/microbiology
• Granuloma/pathology
• Host-Pathogen Interactions
• Humans
• Immunity, Cellular
• Immunity, Humoral
• Immunoglobulin M/biosynthesis
• Immunoglobulin M/immunology
• Lung/immunology
• Lung/microbiology
• Lung/pathology
• Mice
• Mycobacterium tuberculosis/immunology
• Receptors, IgG/genetics
• Receptors, IgG/immunology
• Tuberculosis, Pulmonary/immunology
• Tuberculosis, Pulmonary/microbiology
• Tuberculosis, Pulmonary/pathology

• R01 AI033142 NIAID NIH HHS
• R01 AI098925 NIAID NIH HHS
• AI-105684 NIAID NIH HHS
• R01 AI094745 NIAID NIH HHS
• HL059842 NHLBI NIH HHS
• R37 AI033142 NIAID NIH HHS
• AI098925 NIAID NIH HHS
• T32 AI070117 NIAID NIH HHS
• R01 AI033774 NIAID NIH HHS
• P01 AI063537 NIAID NIH HHS
• AI1094745 NIAID NIH HHS
• R21 AI105684 NIAID NIH HHS
• P30 AI051519 NIAID NIH HHS
• R01 HL059842 NHLBI NIH HHS
• AI51519 NIAID NIH HHS
• AI033142 NIAID NIH HHS
• AI033774 NIAID NIH HHS
• AI-067665 NIAID NIH HHS
• K23 AI067665 NIAID NIH HHS

Continuous support from follicular CD4⁺ T helper (Tfh) cells drives germinal center (GC) responses, which last for several weeks to produce high affinity memory B cells and plasma cells. In autoimmune Sle1 and NZB/W F1 mice, elevated numbers of Tfh cells persist, promoting the expansion of self-reactive B cells. Expansion of circulating Tfh like cells have also been described in several autoimmune diseases. Although, the signals required for Tfh differentiation have now been well described, the mechanisms that sustain the maintenance of fully differentiated Tfh are less understood. Recent data demonstrate a role for GC B cells for Tfh maintenance after protein immunization.

Given the pathogenic role Tfh play in autoimmune disease, we explored whether B cells are required for maintenance of autoreactive Tfh. Our data suggest that the number of mature autoreactive Tfh cells is controlled by GC B cells. Depletion of B cells in Sle1 autoimmune mice leads to a dramatic reduction in Tfh cells. In NZB/W F1 autoimmune mice, similar to the SRBC immunization model, GC B cells support the maintenance of mature Tfh, which is dependent mainly on ICOS. The CD28-associated pathway is dispensable for Tfh maintenance in SRBC immunized mice, but is required in the spontaneous NZB/W F1 model.

These data suggest that mature Tfh cells require signals from GC B cells to sustain their optimal numbers and function in both autoimmune and immunization models. Thus, immunotherapies targeting B cells in autoimmune disease may affect pathogenic Tfh cells.