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CXCR5+PD-1+CD8+ T cells are a distinct sublineage of CD8+ Tfh cells and Stat5 suppresses the expression of the Tfh-specific genes in CXCR5+PD-1+CD8+ T cells [RNA-Seq]

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

ORGANISM(S): Mus musculus

PROVIDER: GSE136640 | GEO | 2019/08/30

REPOSITORIES: GEO

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CXCR5+PD-1+CD8+ T cells are a novel T helper cell sublineage and are negatively regulated by Stat5 [scRNA-Seq]

Project description:Many autoimmune diseases are characterized by the production of autoantibodies. The current view is that CD4+ Tfh cells are the main subset regulating autoreactive B cells. Here, we discover a distinct novel CXCR5+PD1+ Tfh subset of CD8+ T cells whose development and function are negatively regulated by Stat5. These CD8+ Tfh cells regulate the GC B cell response and control autoantibody production. Deficiency of Stat5 in CD8+ T cells leads to an increase of CD8+ Tfh cells, resulting in the breakdown of B cell tolerance and autoantibody production. CD8+ Tfh share similar gene signatures with CD4+ Tfh and require CD40L/CD40 and TCR/MHCI interactions to deliver help to B cells. Our study highlights the diversity of follicular T cell subsets that contribute to the breakdown of B-cell tolerance

2019-08-30 | GSE136641 | GEO

CXCR5+PD-1+CD8+ T cells are a distinct sublineage of CD8+ Tfh cells and Stat5 suppresses the expression of the Tfh-specific genes in CXCR5+PD-1+CD8+ T cells [RNA-Seq]

Project description:CXCR5+PD-1+CD8+ T cells are a distinct sublineage of CD8+ Tfh cells and Stat5 suppresses the expression of the Tfh-specific genes in CXCR5+PD-1+CD8+ T cells [RNA-Seq]

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Gene expression of CD4+CD8+ Tfh cells and CD4+CD8- Tfh in tonsil.

Project description:To understand physiological characteristics of CD4+CD8+ Double-positive (DP)-Tfh cells, we continued to conduct comparative transcriptome analysis of tonsillar Tfh cell populations, including DP-Tfh cells and CD4+CD8- single-positive (SP)-Tfh cells as a control. Results showed that DP-Tfh cells preferentially expressed transcripts related to CTLs, such as CD8 (CD8A and CD8B), Eomes, and granzymes, suggesting a possible cytotoxic attribute of DP-Tfh cells. Th1-cell related signature genes were also presented in DP-Tfh cells and cytokines like interferon (IFN)-gamma and interleukin (IL)-10 were found to be highly presented in DP-Tfh cells rather than SP-Tfh cells. Of note, the expression profile of authentic Tfh-cell (i.e. SP-Tfh cell) related genes like IL-4, IL-21, Bcl6, and Pou2af1 seemed to be shared with DP-Tfh cells.

2022-08-10 | GSE202616 | GEO

Gene expression of CD4+CD8+ Tfh cells and CD4+CD8- Tfh in tonsil.

Project description:Gene expression of CD4+CD8+ Tfh cells and CD4+CD8- Tfh in tonsil.

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Defining memory-like CD8 T cells that respond to PD-1 therapy in chronic viral infection

Project description:Chronic viral infections are characterized by a state of CD8 T cell dysfunction termed exhaustion. A better understanding of the mechanisms that regulate CD8 T cell responses during chronic infection is required to improve immunotherapies that restore function in exhausted CD8 T cells. Here we identify a novel population of virus-specific CD8 T cells with a T follicular helper (Tfh)-like signature in mice chronically infected with lymphocytic choriomeningitis virus (LCMV). These Tfh-like CD8 T cells expressed the programmed cell death-1 (PD-1) inhibitory receptor but at the same time also expressed co-stimulatory molecules and had a gene signature that was related to CD8 T cell memory precursor cells and hematopoietic stem cells (HSC). These Tfh-like CD8 T cells acted as stem cells during chronic infection undergoing self-renewal and also differentiating into the terminally exhausted CD8 T cells that were present in both lymphoid and non-lymphoid tissues. The Tfh-like CD8 T cells were found only in lymphoid tissues and resided predominantly in the T cell zones along with naÃ¯ve CD8 T cells. Interestingly, the proliferative burst after PD-1 blockade came almost exclusively from this Tfh-like CD8 T cell subset. Importantly, the transcription factor TCF1 played a cell intrinsic and essential role in the generation of Tfh-like CD8 T cells. Taken together, our study identifies Tfh-like CD8 T cells as the critical subset for maintaining the pool of virus-specific CD8 T cells during chronic infection and as the cells that proliferate after PD-1 blockade. These findings provide a better understanding of T cell exhaustion and have implications towards optimizing PD-1 directed immunotherapy. 8 samples isolated from CD8 T-cells in LCMV clone 13 GK1.5 infected mice (2 naÃ¯ve, 3 CXCR5+Tim3-, 3 CXCR5-Tim3+) cells were analyzed

2016-08-02 | E-GEOD-84105 | biostudies-arrayexpress

Transcription profiling of mouse Splenic CD4+CXCR5+ T (TFH) cells

Project description:After activation, CD4+ helper T (Th) cells differentiate; into distinct effector subsets. Although chemokine; (C-X-C motif) receptor 5-expressing T follicular; helper (Tfh) cells are important in humoral immunity,; their developmental regulation is unclear. Here we; show that Tfh cells had a distinct gene expression; profile and developed in vivo independently of the; Th1 or Th2 cell lineages. Tfh cell generation was regulated; by ICOS ligand (ICOSL) expressed on B cells; and was dependent on interleukin-21 (IL-21), IL-6,; and signal transducer and activator of transcription; 3. However, unlike Th17 cells, differentiation of Tfh; cells did not require transforming growth factor; b (TGF-b) or Th17-specific orphan nuclear receptors; RORa and RORg in vivo. Finally, naive T cells activated; in vitro in the presence of IL-21 but not; TGF-b signaling preferentially acquired Tfh gene; expression and promoted germinal-center reactions; in vivo. This study thus demonstrates that Tfh is a; distinct Th cell lineage. Experiment Overall Design: Splenic CD4+CXCR5+ T cells were isolated from KLH-immunized mice and restimulated with anti-CD3 for 4 hours before total RNA preparation. Affymetrix gene chips were used to analyze their gene expression.

2008-10-21 | E-GEOD-11924 | biostudies-arrayexpress

Gene expression of CD4+CD8+ Tfh cells in lesions of IgG4-related disease and CD4+CD8+ Tfh in tonsil.

Project description:To further know features of CD4+CD8+ Double positive (DP)-Tfh cells in respective lymphoid tissues, we subsequently investigated transcriptomes of DP-Tfh cells in submandibular gland lesions of IgG4-RD in comparison to those of DP-Tfh cells in tonsils. Results showed that DP-Tfh cells of IgG4-RD lesions were more apt to present CTL-related genes such as Eomes and granzymes than DP-Tfh cells in tonsils. It was also noted that the level of CD70 in DP-Tfh cells of IgG4-RD lesions was higher than that of tonsillar DP-Tfh cells. Genes related to Tfh cell function were seemed to be presented in DP-Tfh cells of tonsils compared to DP-Tfh cells of IgG4-RD lesions.

2022-08-10 | GSE202617 | GEO

Circulating CXCR5+CXCR3+PD-1Lo Tfh-like cells in HIV-1 controllers with neutralizing antibody breadth

Project description:HIV-1-specific broadly-neutralizing antibodies (bnAb) typically develop in individuals with continuous high-level viral replication and increased immune activation, conditions that cannot be reproduced during prophylactic immunization. Understanding mechanisms supporting bnAb development in the absence of high-level viremia may be important for designing bnAb-inducing immunogens. Here, we show that the breadth of neutralizing antibody responses in HIV-1 controllers was associated with a relative enrichment of circulating CXCR5+ CXCR3+ PD-1Lo CD4 T cells. These CXCR3+ PD-1Lo Tfh-like cells were preferentially induced in vitro by functionally superior dendritic cells from controller neutralizers, and able to secrete IL-21 and support B cells. In addition, these CXCR3+ PD-1Lo Tfh-like cells contain higher proportions of stem cell-like memory T cells, and upon antigenic stimulation differentiated into PD-1Hi Tfh-like cells in a Notch-dependent manner. Together, these data suggest that CXCR5+ CXCR3+ PD-1Lo cells represent a dendritic cell-primed precursor cell population for PD-1Hi Tfh-like cells that may contribute to the generation of bnAbs in the absence of high–level viremia.

2017-02-01 | GSE90897 | GEO

Intratumoral mregDC and Tfh-like niches enable local reinvigoration of CD8 T cells following PD-1 blockade

Project description:While T cell accumulation in tumors is associated with response to immune checkpoint blockade (ICB), many T cell-rich tumors fail to respond to ICB. Here we leveraged a large neoadjuvant PD-1 blockade trial in hepatocellular carcinoma (HCC) to search for correlates of ICB response within T cell-rich tumors. Paired scRNAseq/TCRseq of nearly one million immune cells revealed that tumor responses to ICB correlated with significant clonal expansion of intratumoral CH25H+CXCL13+IL-21+CD4 T cells and GranzymeK+PD-1+CD8 effector T cells, whereas terminally exhausted CD39hiToxhiPD-1hi CD8 clones dominated in non-responders. Notably, proliferating and progenitor CD8 T cells clones were found in tumors of responders and non-responders. However, tumors from responders were highly enriched in mregDCs, a DC state triggered by capture of tumor debris, which formed physically interacting cellular triads with Tfh-like CD4 and progenitor-like CD8 T cells. Receptor-ligand analysis revealed unique interactions within these triads that may promote progenitor CD8 T cell differentiation into effector cells upon PD-1 blockade. These results suggest that discrete cellular niches that include mregDCs and Tfh-like CD4 T cells might control the differentiation of tumor-specific progenitor CD8 T cell clones into effective anti-tumor T cells in human tumors.

2023-06-16 | GSE206325 | GEO

Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy

Project description:Chronic viral infections are characterized by a state of CD8 T cell dysfunction termed exhaustion. A better understanding of the mechanisms that regulate CD8 T cell responses during chronic infection is required to improve immunotherapies that restore function in exhausted CD8 T cells. Here we identify a novel population of virus-specific CD8 T cells with a T follicular helper (Tfh)-like signature in mice chronically infected with lymphocytic choriomeningitis virus (LCMV). These Tfh-like CD8 T cells expressed the programmed cell death-1 (PD-1) inhibitory receptor but at the same time also expressed co-stimulatory molecules and had a gene signature that was related to CD8 T cell memory precursor cells and hematopoietic stem cells (HSC). These Tfh-like CD8 T cells acted as stem cells during chronic infection undergoing self-renewal and also differentiating into the terminally exhausted CD8 T cells that were present in both lymphoid and non-lymphoid tissues. The Tfh-like CD8 T cells were found only in lymphoid tissues and resided predominantly in the T cell zones along with naïve CD8 T cells. Interestingly, the proliferative burst after PD-1 blockade came almost exclusively from this Tfh-like CD8 T cell subset. Importantly, the transcription factor TCF1 played a cell intrinsic and essential role in the generation of Tfh-like CD8 T cells. Taken together, our study identifies Tfh-like CD8 T cells as the critical subset for maintaining the pool of virus-specific CD8 T cells during chronic infection and as the cells that proliferate after PD-1 blockade. These findings provide a better understanding of T cell exhaustion and have implications towards optimizing PD-1 directed immunotherapy.

2023-03-18 | GSE227399 | GEO

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