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CXCR5+PD-1+ follicular helper CD8 T cells control B cell tolerance.

ABSTRACT: Many autoimmune diseases are characterized by the production of autoantibodies. The current view is that CD4+ T follicular helper (Tfh) cells are the main subset regulating autoreactive B cells. Here we report a CXCR5+PD1+ Tfh subset of CD8+ T cells whose development and function are negatively modulated by Stat5. These CD8+ Tfh cells regulate the germinal center B cell response and control autoantibody production, as deficiency of Stat5 in CD8 T cells leads to an increase of CD8+ Tfh cells, resulting in the breakdown of B cell tolerance and concomitant autoantibody production. CD8+ Tfh cells share similar gene signatures with CD4+ Tfh, and require CD40L/CD40 and TCR/MHCI interactions to deliver help to B cells. Our study thus highlights the diversity of follicular T cell subsets that contribute to the breakdown of B-cell tolerance.

SUBMITTER: Chen Y

PROVIDER: S-EPMC6765049 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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CXCR5+PD-1+ follicular helper CD8 T cells control B cell tolerance.

Chen Yuhong Y Yu Mei M Zheng Yongwei Y Fu Guoping G Xin Gang G Zhu Wen W Luo Lan L Burns Robert R Li Quan-Zhen QZ Dent Alexander L AL Zhu Nan N Cui Weiguo W Malherbe Laurent L Wen Renren R Wang Demin D

Nature communications 20190927 1

Many autoimmune diseases are characterized by the production of autoantibodies. The current view is that CD4+ T follicular helper (Tfh) cells are the main subset regulating autoreactive B cells. Here we report a CXCR5+PD1+ Tfh subset of CD8+ T cells whose development and function are negatively modulated by Stat5. These CD8+ Tfh cells regulate the germinal center B cell response and control autoantibody production, as deficiency of Stat5 in ...[more]

PMID: 31562329

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CXCR5+PD-1+ follicular helper CD8 T cells control B cell tolerance

Project description:This SuperSeries is composed of the SubSeries listed below.

2019-08-30 | GSE136642 | GEO

The diagnostic role of PD-1+ CXCR5+ follicular helper CD8+ T cell in renal allograft dysfunction.

Project description:BackgroundThe roles of PD-1+ CXCR5+ follicular helper CD8+ T cell were reported in different disease conditions, but their roles in transplantation are unclear. In this study, the association between PD-1+ CXCR5+ follicular helper CD8+ T cell and renal allograft dysfunction in kidney transplant recipients (KTRs) was investigated.Methods82 KTRs were enrolled in this study. 45 KTRs were included in the chronic allograft dysfunction (CAD) group, and 37 KTRs were included in the stable recipients group. Among the CAD group, 12 cases of antibody-mediated rejection (ABMR) and 4 cases of T cell-mediated rejection (TCMR) were diagnosed by biopsy. The percentage of CXCR5+ CD8+ T cells and the co-expression of signal transducers and activators of transcription 4 (STAT4), STAT5, and PD-1 in peripheral blood were determined by flow cytometry.ResultsThe expression of CXCR5 on CD3+ CD8+ T cells and the percentage of STAT5+ CXCR5+ cells in the CD3+ CD8+ T-cell population were significantly lower in the CAD group (p < 0.05), while the expression of PD-1+ CXCR5+ CD8+ T cells was significantly higher (p < 0.05). Through logistic regression analysis, we concluded that the percentage of PD-1+ CXCR5+ CD8+ T cells was an independent risk factor for renal dysfunction. Grouping by pathological type, PD-1+ CXCR5+ CD8+ T cells showed relatively good diagnostic efficacy for ABMR by ROC analysis.ConclusionsOur results suggested that PD-1+ CXCR5+ CD8+ T cells were a promising biomarker for distinguishing renal allograft dysfunction and different allograft pathological types. Also, our findings may provide new ways of identifying and treating allograft rejection.

| S-EPMC8842189 | biostudies-literature

CXCR5+PD-1+ follicular helper CD8 T cells control B cell tolerance

Project description:CXCR5+PD-1+ follicular helper CD8 T cells control B cell tolerance

| PRJNA562906 | ENA

Primary germinal center-resident T follicular helper cells are a physiologically distinct subset of CXCR5hiPD-1hi T follicular helper cells.

Project description:T follicular helper (Tfh) cells are defined by a Bcl6+CXCR5hiPD-1hi phenotype, but only a minor fraction of these reside in germinal centers (GCs). Here, we examined whether GC-resident and -nonresident Tfh cells share a common physiology and function. Fluorescently labeled, GC-resident Tfh cells in different mouse models were distinguished by low expression of CD90. CD90neg/lo GCTfh cells required antigen-specific, MHCII+ B cells to develop and stopped proliferating soon after differentiation. In contrast, nonresident, CD90hi Tfh (GCTfh-like) cells developed normally in the absence of MHCII+ B cells and proliferated continuously during primary responses. The TCR repertoires of both Tfh subsets overlapped initially but later diverged in association with dendritic cell-dependent proliferation of CD90hi GCTfh-like cells, suggestive of TCR-dependency seen also in TCR-transgenic adoptive transfer experiments. Furthermore, the transcriptomes of CD90neg/lo and CD90hi GCTfh-like cells were enriched in different functional pathways. Thus, GC-resident and nonresident Tfh cells have distinct developmental requirements and activities, implying distinct functions.

| S-EPMC8842852 | biostudies-literature

Protective role of follicular CXCR5+CD8+ T cells against dengue virus 2 infection.

Project description:Follicular CXCR5+CD8+ T cells have antiviral effects in chronic virus infection, but the roles of these cells during dengue virus 2 (DENV2) infection remain poorly understood.ObjectiveThis study was conducted to analyzed in detail the dynamic changes and functional properties of circulating follicular CXCR5+CD8+ T cells to explore their effects on DENV2 infection.MethodsCirculating follicular CXCR5+CD8+ T cells and cytokines were analyzed by flow cytometry in DENV2 patients at difference days after DENV2 infection. CD8+ T cells were isolated and purified from DENV2 patients, then were stimulated with NS1 peptides and TCR stimulant. After cultivation, multiple parameters were tested.Results(1) CXCR5+CD8+ T cells emerged after DENV2 infection, with high PD-1 expression, and were correlated with the reduction in DENV2 RNA viral loads. (2) PD-1+CXCR5+CD8+ T cells were negatively associated with disease progression. (3) Serum IFN-γ, IL-6 and IL-10 levels were increased late in the course of DENV2 infection. (4) CXCR5+CD8+ T cells from DENV2 patients exhibited increased cytotoxicity and IFN-γ and IL-10 secretion.ConclusionCXCR5+CD8+ T cells could play a protective role in dengue pathogenesis and may be a novel strategy for controlling DENV2 infection and vaccine development.

| S-EPMC7110549 | biostudies-literature

Follicular helper-T cells restore CD8+-dependent antitumor immunity and anti-PD-L1/PD-1 efficacy.

Project description:T follicular helper cells (Tfh) are essential to shape B cell response during germinal center formation. Tfh accumulation has been reported in various human cancers, with positive or negative prognostic roles. However, the mechanisms explaining the accumulation of Tfh and their role in cancer remain obscure. In vitro differentiated and mouse cell sorted Tfh phenotype was evaluated by flow cytometry and quantitative PCR (qPCR). Antitumor effect of Tfh was evaluated by adoptive transfer in different tumor-bearing mice models. The involvement of immune cells, cytokines and chemokines was evaluated, using depleting antibodies. Chemokines and cytokines expression and production were evaluated by qPCR and ELISA. In human, the impact of immune cells and chemokines on survival was evaluated by analyzing transcriptomic data from public databases and from our own patient cohorts. In this study, we show that Tfh exert an antitumor immune effect in a CD8+-dependent manner. Tfh produce interleukin-21, which sustains proliferation, viability, cytokine production and cytotoxic functions of exhausted T cells. The presence of Tfh is required for efficacy of antiprogrammed cell death ligand-1 therapy. Tfh accumulate in the tumor bed and draining lymph nodes in different mouse cancer models. This recruitment is due to the capacity of transforming growth factor β to drive Chemokine (C-X-C motif) Ligand 13 expression, a chemoattractant of Tfh, by intratumor CD8+ T cells. Accumulation of Tfh and exhausted CD8+ T cells predicts cancer outcome in various cancer types. In patients treated with anti-programmed cell death-1 mAb, accumulation of Tfh and CD8+ at the tumor site is associated with outcome. This study provides evidence that CD8+/Tfh crosstalk is important in shaping antitumor immune response generated by immunotherapy.

| S-EPMC8190041 | biostudies-literature

CD4+CD8+ T follicular helper cells regulate humoral immunity in chronic inflammatory lesions.

Project description:T follicular helper (Tfh) cells drive humoral immunity by facilitating B cell responses at the initial and recall phases. Recent studies have indicated the possible involvement of Tfh cells in the process of chronic inflammation. However, the functional role of Tfh cells in persistent immune settings remains unclear. Here, we report that CD4+CD8+ (double-positive, DP; CD3+CD4+CD8+CXCR5hiPD-1hi) Tfh cells, a subset of germinal-center-type Tfh cells, were abundantly present in the fibroinflammatory lesions of patients with immunoglobulin G4-related disease (IgG4-RD). Transcriptome analyses showed that these DP-Tfh cells in the lesions of IgG4-RD preferentially expressed signature genes characteristic of cytotoxic CD8+ T cells, such as Eomes, CRTAM, GPR56, and granzymes, in addition to CD70. Scatter diagram analyses to examine the relationships between tissue-resident lymphocytes and various clinical parameters revealed that the levels of DP-Tfh cells were inversely correlated to the levels of serum IgG4 and local IgG4-expressing (IgG4+) memory B cells (CD19+CD27+IgD-) in patients with IgG4-RD. Cell culture experiments using autologous tonsillar lymphocytes further suggested that DP-Tfh cells possess a poor B-cell helper function and instead regulate memory B cells. Since CD4+ (single positive, SP; CD3+CD4+CD8-CXCR5hiPD-1hi) Tfh cells differentiated into DP-Tfh cells under stimulation with IL-2 and IL-7 as assessed by in vitro experiments, these data imply that SP-Tfh cells are a possible origin of DP-Tfh cells under persistent inflammation. These findings highlight the potential feedback loop mechanism of Tfh cells in immune tolerance under chronic inflammatory conditions. Further studies on DP-Tfh cells may facilitate control of unresolved humoral responses in IgG4-RD pathological inflammation.

| S-EPMC9452889 | biostudies-literature

Human CXCR5+ PD-1+ CD8 T cells in healthy individuals and patients with hematologic malignancies.

Project description:Immune checkpoint blockade (ICB) has revolutionized cancer therapy, but varying response rates illustrate the need for biomarkers of response. Studies in mice have identified a subset of CD8 T cells that is essential for response to PD-1 ICB. These CD8 T cells co-express CXCR5, PD-1 and Tcf1, and provide effector T cells upon PD-1 ICB. It is unknown whether similar T cells play a role in PD-1 ICB in humans. We studied human peripheral blood and lymph nodes (LNs) for the frequency, phenotype, and functionality of CXCR5+ PD-1+ CD8 T cells. We find that CXCR5+ PD-1+ CD8 T cells are memory-like cells, express Tcf1, and lack expression of effector molecules. CXCR5+ PD-1+ CD8 T cells produce cytokines upon stimulation, but have limited proliferative capacity. We studied patients with hematologic malignancies with varying response rates to PD-1 ICB. Specifically in chronic lymphocytic leukemia, in which PD-1 ICB does not induce clinical responses, CXCR5+ PD-1+ CD8 T cells show loss of the memory phenotype and increased effector differentiation. In conclusion, we identified CXCR5+ PD-1+ CD8 T cells in human peripheral blood and LN, which could play a similar role during PD-1 ICB. Future studies should analyze CXCR5+ PD-1+ CD8 T cells during PD-1 ICB and their importance for therapeutic response.

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Inhibition of follicular T-helper cells by CD8(+) regulatory T cells is essential for self tolerance.

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The transcription factor Runx3 guards cytotoxic CD8+ effector T cells against deviation towards follicular helper T cell lineage.

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