Next-generation sequencing of Tfh cells from CSF compared to paired blood in multiple sclerosis
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE173084 | GEO | 2022/10/28
REPOSITORIES: GEO
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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
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Project description:In this experiment we generated Affymetrix gene expression data for T Follicular Helper (TFH) cells from tonsils of healthy volunteers (4 biological replicates) and naive CD4-positive helper T cells (2 biological replicates). TFH cells provide a model relevant to SLE as TFH operate upstream of the activation of pathogenic autoantibody-producing B cells during the disease. This experiment accompanies promoter capture-C and ATAC-seq experiments on the same cell types.
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2010-04-28 | E-GEOD-21380 | biostudies-arrayexpress
Project description:CD4 T cell help is critical for both the generation and maintenance of germinal centers, and T follicular helper (TFH) cells are the CD4 T cell subset required for this process. SAP (SH2D1A) expression in CD4 T cells is essential for germinal center development. However, SAP-deficient mice have only a moderate defect in TFH differentiation as defined by common TFH surface markers. CXCR5+ TFH cells are found within the germinal center as well as along the boundary regions of T/B cell zones. Here we show that germinal center associated T cells (GC TFH) can be identified by their co-expression of CXCR5 and the GL7 epitope, allowing for phenotypic and functional analysis of TFH and GC TFH populations. Here we show GC TFH are a functionally discrete subset of further polarized TFH cells, with enhanced B cell help capacity and a specialized ability to produce IL-4 in a TH2-independent manner. Strikingly, SAP-deficient mice have an absence of the GC TFH subset and SAP- TFH are defective in IL-4 and IL-21 production. We further demonstrate that SLAM (Slamf1, CD150), a surface receptor that utilizes SAP signaling, is specifically required for IL-4 production by GC TFH. GC TFH cells require IL-4 and IL-21 production for optimal help to B cells. These data illustrate complexities of SAP-dependent SLAM family receptor signaling, revealing a prominent role for SLAM receptor ligation in IL-4 production by germinal center CD4 T cells but not in TFH and GC TFH differentiation.
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Project description:The meningeal space is an important structure in the brain borders, which provides immunosurveillance for the central nervous system, but the impact of infections on the meningeal immune landscape is far from being fully understood. Trypanosoma brucei, the causative agents of Human African Trypanosomiasis or sleeping sickness, accumulates in the meningeal spaces, inducing severe meningitis and resulting in death if left untreated. Thus, sleeping sickness represents an attractive model to study immunological dynamics in the meninges during infection. Here, combining single cell transcriptomics and mass cytometry by time of flight (CyTOF), coupled with in vivo interventions, we found that chronic T. brucei infection triggers the development of ectopic lymphoid aggregates (ELAs) in the murine meninges during chronic infection. These infection-induced ectopic structures are defined by the presence of ER-TR7+ fibroblastic reticular cells (FRCs) and follicular dendritic cells (FDCs) that initiate a signalling cascade driving local T cell activation towards a T follicular helper (TFH)-like phenotype, as well as B cell class switching. Furthermore, the meningeal-resident plasma cells display activity typically associated with germinal centre reactions and are able to produce antibodies able to recognise mouse brain antigens, which correlates with cortical (and white matter) demyelination. Lastly, we found that systemic lymphotoxin (LT) signalling blockade led to a significant depletion of meningeal FDCs and autoreactive B cells, indicating that LTsignalling is critical to induce and maintain local responses in the meninges. Taken together, we provide evidence that the meningeal immune response results in the acquisition of lymphoid tissue-like properties during chronic T. brucei infection. These findings have broader implications for understanding the mechanisms underlying the formation ELAs during chronic inflammation resulting in autoimmunity, as observed in other demyelinating neurodegenerative disorders such as multiple sclerosis.
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Project description:Follicular helper T (Tfh) cells access the B cell follicle to promote antibody responses, and are particularly important for germinal center (GC) reactions. However, the molecular mechanisms of how Tfh cells are physically associated with GCs are incompletely understood. Here we report that the sphingosine-1-phosphate receptor 2 (S1PR2) gene is highly expressed in a subpopulation of Tfh cells that localizes in GCs. S1PR2-deficient Tfh cells exhibited reduced accumulation in GCs due to their impaired retention. T cells deficient in both S1PR2 and CXCR5 were ineffective in supporting GC responses compared to T cells deficient only in CXCR5. These results suggest that S1PR2 and CXCR5 cooperatively regulate localization of Tfh cells in GCs to support GC responses. Venus-high Tfh, Venus-low Tfh, PD1-intermediate Th, PD1-low Th and naïve CD4+ T cells were sorted on FACSAria from immunized S1pr2V/+ mice or control mice for RNA extraction and hybridization on Affimetrix microarrays.
2014-05-30 | E-GEOD-56883 | biostudies-arrayexpress
Project description:T follicular helper (Tfh) cells, essential for germinal center reactions, are not identical, with different phenotypes reported. Whether, when and how they generate memory cells are still poorly understood. Here, through single-cell RNA-sequencing analysis of CXCR5+Bcl6+ Tfh cells generated under different conditions, we discovered, in addition to PD-1hi effector Tfh cells, a CD62L+PD1low subpopulation. CD62L-expressing Tfh cells developed independently from PD-1+ cells, and not in direct contact with B cells. More importantly, CD62L+ Tfh cells expressed memory- and stemness-associated genes; with more superior long-term survival, they readily generated PD-1hi cells in the recall response. Finally, KLF2 and IL7R, also highly expressed by CD62L+ Tfh cells, were required to regulate their development. Our work thus demonstrates a novel Tfh memory-like cell subpopulation, which may benefit our understanding on immune responses and diseases.
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