SLAM/SAP signaling regulates discrete γδ T cell developmental checkpoints and shapes the innate-like γδ TCR repertoire
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ABSTRACT:
PROVIDER: PRJNA1090116 | ENA |
REPOSITORIES: ENA
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Project description:During thymic development, most γδ T cells acquire innate-like characteristics that are critical for their function in tumor surveillance, infectious disease, and tissue repair. The mechanisms, however, that regulate γδ T cell developmental programming remain unclear. Recently, we demonstrated that the SLAM-SAP signaling pathway regulates the development and function of multiple innate-like γδ T cell subsets. Here, we used a single-cell proteogenomics approach to identify SAP-dependent developmental checkpoints and to define the SAP-dependent γδ TCR repertoire. SAP deficiency resulted in both a significant loss of an immatureGzma+Blk+Etv5+Tox2+γδT17 precursor population, and a significant increase inCd4+Cd8+Rorc+Ptcra+Rag1+thymic γδ T cells. SAP-dependent diversion of embryonic day 17 thymic γδ T cell clonotypes into the αβ T cell developmental pathway was associated with a decreased frequency of mature clonotypes in neonatal thymus, and an altered γδ TCR repertoire in the periphery. Finally, we identify TRGV4/TRAV13-4(DV7)-expressing T cells as a novel, SAP-dependent Vγ4 γδT1 subset. Together, the data suggest that SAP-dependent γδ/αβ T cell lineage commitment regulates γδ T cell developmental programming and shapes the γδ TCR repertoire.
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Project description:A common genetic variant in the gene encoding the protein tyrosine phosphatase nonreceptor type 22 (PTPN22 C1858T) has been linked to a wide range of autoimmune disorders. Although a B cell-intrinsic role in promoting disease has been reported, the mechanism(s) through which this variant functions to alter the preimmune B cell repertoire remains unknown. Using a series of polyclonal and transgenic self-reactive models harboring the analogous mutation in murine Ptpn22, we show evidence for enhanced BCR, B cell-activating factor receptor, and CD40 coreceptor programs, leading to broadly enhanced positive selection of B cells at two discrete checkpoints in the bone marrow and spleen. We further identified a bias for selection of B cells into the follicular mature versus marginal zone B cell compartment. Using a biomarker to track a self-reactive H chain in peripheral blood, we found evidence of similarly enhanced positive selection in human carriers of the PTPN22 C1858T variant. Our combined data support a model whereby the risk variant augments the BCR and coreceptor programs throughout B cell development, promoting enrichment of self-reactive specificities into the follicular mature compartment and thereby likely increasing the risk for seeding of autoimmune B cell responses.
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2011-04-06 | E-GEOD-28437 | biostudies-arrayexpress
Project description:RNA expression of unstimulated γδ-T cells,γδ-TCR-stimulated γδ-T cells, unstimulated αβ-TCR transduced γδ-T cells and αβ-TCR-stimulated αβ-TCR transduced γδ-T cells.
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2023-07-20 | PXD039463 | Pride
Project description:The murine thymus produces discrete γδ T cell subsets making either IFN-γ or IL-17, but the role of the TCR in this developmental process remains controversial. Here we generated a non-transgenic and polyclonal model of reduced TCR expression and signal strength selectively on γδ T cells. Mice haploinsufficient for both CD3γ and CD3δ (CD3DH) showed normal αβ thymocyte subsets but specific defects in γδ T cell development, namely impaired differentiation of IL-17-producing embryonic Vγ6+ (but not adult Vγ4+) γδ T cells and a marked depletion of IFN-γ-producing CD122+ NK1.1+ (Vγ1-biased) γδ T cells throughout life. As result, adult CD3DH mice showed defective peripheral IFN-γ responses and were resistant to experimental cerebral malaria. Thus, strong TCR signaling is required within specific developmental windows with distinct Vγ usage and differential cytokine production by effector γδ T cell subsets.
2016-03-29 | GSE71637 | GEO
Project description:Here, we discovered that the frequency of CD39+γδ Tregs, which positively correlated with poor prognosis, was significantly higher in right-sided colorectal cancer (RSCRC) than in the left-sided CRC (LSCRC). To explore the molecular mechanism leading to the difference of CD39+γδ Tregs derived from RSCRC and LSCRC, we collected fresh tissue samples of RSCRC with high expression of CD39+γδ Tregs and the LSCRC with low expression of CD39+γδ Tregs detected by flow cytometry and identified differential proteins by LC-MS based quantitative proteomic analysis with tandem mass tag (TMT)
2022-02-17 | PXD027323 | Pride
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. This SuperSeries is composed of the following subset Series: GSE21379: Expression Data from WT and Sh2d1a-/- in vivo follicular helper CD4 T cells (TFH) versus non follicular helper CD4 T cells (non-TFH) GSE21380: Expression Data from in vivo Tfh vs GC Tfh vs non-Tfh Refer to individual Series
2010-04-28 | E-GEOD-21381 | biostudies-arrayexpress
Project description:Abstract: Bovine tuberculosis (bTB), caused by infection with Mycobacterium bovis, continues to cause significant issues for the global agriculture industry as well as for human health. An incomplete understanding of the host immune response contributes to the challenges of control and eradication of this zoonotic disease. In this study, high-throughput bulk RNA sequencing (RNA-seq) was used to characterize differential gene expression in γδ T cells – a subgroup of T cells which bridge innate and adaptive immunity and have specific anti-mycobacterial response mechanisms. γδ T cell subsets are classified on the basis of expression of a pathogen-recognition receptor known as Workshop Cluster 1 (WC1) and we hypothesised that bTB infection may alter the phenotype and function of specific γδ T cell subsets. Peripheral blood was collected from naturally M. bovis-infected (positive for single intradermal comparative tuberculin test (SICTT) and IFN-γ ELISA) and age- and sex-matched, non-infected control Holstein-Friesian cattle. γδ T subsets were isolated using fluorescence activated cell sorting (n = 10-12 per group) and high-quality RNA extracted from each purified lymphocyte subset (WC1.1+, WC1.2+, WC1- and γδ-) was used to generate transcriptomes using bulk RNA-seq (n = 6 per group, representing a total of 48 RNA-seq libraries). Relatively low numbers of differentially expressed genes (DEGs) were observed between most cell subsets; however, 163 genes were significantly differentially expressed in the M. bovis-infected compared to control groups for the WC1.1+ γδ T cell compartment (Log 2 FC ≥ 1.5 and FDR P adj ≤ 0.1). The majority of these DEGs (146) were significantly increased in expression in cells from the bTB+ cattle and included genes encoding transcription factor (TBX21 and EOMES), chemokine receptors (CCR5 and CCR7), granzymes (GZMA, GZMM and GZMH) and multiple killer cell immunoglobulin-like receptors (KIR) indicating cytotoxic functions. Biological pathway overrepresentation analysis revealed enrichment of genes with multiple immune functions including cell activation, proliferation, chemotaxis and cytotoxicity of lymphocytes. In conclusion, WC1.1+ γδ T cells have been proposed as major regulatory cell subset in cattle, and we provide evidence for preferential differential activation of this specific subset in cattle naturally infected with M. bovis. Understanding the role of these critical immune cells during mycobacterial infection contributes to our understanding of host immunity to bTB and identifies multiple novel cytotoxic functions of WC1.1+ γδ T cells.
2023-07-01 | E-MTAB-13111 | biostudies-arrayexpress
Project description:A new method of graft manipulation based on physical removal of αβ+ T cells and CD19+ B cells, leaving mature NK cells and γδ T cells in the graft, has been recently developed for HLA-haploidentical HSCT. We demonstrated that γδ T cells collected from transplanted patients are endowed with capacity of killing leukemia cells after ex vivo treatment with zoledronic acid (ZOL). Thus, we hypothesized that infusion of ZOL in patients receiving this type of graft, may boost γδ T cell cytotoxic activity against acute leukemia blasts.
2018-10-24 | PXD002629 | Pride