CD226 and TIGIT cooperate in the differentiation and maturation of human Tfh cells
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE194293 | GEO | 2022/02/16
REPOSITORIES: GEO
Similar Datasets
Project description:CD226 and TIGIT cooperate in the differentiation and maturation of human Tfh cells
| PRJNA800075 | ENA
Project description:Costimulation pathways play an essential role in T cell activation, differentiation, and regulation. CD155 expressed on antigen-presenting cells (APCs) interacts with TIGIT, an inhibitory costimulatory molecule, and CD226, an activating costimulatory molecule, on T cells. TIGIT and CD226 are expressed at varying levels depending on the T cell subset and activation state. T follicular helper cells in germinal centers (GC-Tfh) in human tonsils express high TIGIT and low CD226. However, the biological role of the CD155/TIGIT/CD226 axis in human Tfh cell biology has not been elucidated. To address this, we analyzed tonsillar CD4+ T cell subsets cultured with artificial APCs constitutively expressing CD155. Here we show that CD226 signals promote the early phase of Tfh cell differentiation in humans. CD155 signals promoted the proliferation of naïve CD4+ T cells and Tfh precursors (pre-Tfh) isolated from human tonsils and upregulated multiple Tfh molecules and decreased IL-2, a cytokine detrimental for Tfh cell differentiation. Blocking CD226 potently inhibited their proliferation and expression of Tfh markers. By contrast, while CD155 signals promoted the proliferation of tonsillar GC-Tfh cells, their proliferation required only weak CD226 signals. Furthermore, attenuating CD226 signals rather increased the expression of CXCR5, ICOS, and IL-21 by CD155-stimulated GC-Tfh cells. Thus, the importance of CD226 signals changes according to the differentiation stage of human Tfh cells and wanes in mature GC-Tfh cells. High TIGIT expression on GC-Tfh may play a role in attenuating the detrimental CD226 signals post GC-Tfh cell maturation.
| S-EPMC8902812 | biostudies-literature
Project description:Understanding human Regulatory T cell (Treg) heterogeneity may identify markers of disease pathogenesis and facilitate the development of optimized cellular therapeutics. Previous analysis revealed that the co-inhibitory receptor T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) was highly expressed on tTreg. The negative regulator TIGIT and the co-stimulatory factor CD226 bind the common ligand CD155. Human regulatory T cells (CD4+CD25+CD127-/lo) from adult peripheral blood were sub-fractionated based on the markers CD226 and TIGIT and were subsequently expanded in vitro according to clinical expansion protocols. The transcriptional profile of the final cell products uncovered considerable heterogeneity in terms of in vitro expansion and suppressive capacity. Most notably, the CD226+TIGIT- fraction adopted a transcriptional profile most similar to that of conventional T cells, including the capacity for effector cytokine production. Tregs and corresponding Tconv were expanded from peripheral blood of three normal healthy control male subjects.
2015-04-30 | E-GEOD-62015 | biostudies-arrayexpress
Project description:B cell depletion in patients with relapsing remitting multiple sclerosis (RRMS) markedly prevents new MRI lesions and disease activity, suggesting the hypothesis that altered B cell function leads to the activation of T cells driving disease pathogenesis. Here, we performed comprehensive analyses of memory B cells from patients with MS and healthy age-matched controls stimulated with CD40L and IL-21, modeling the help of follicular helper T cells (Tfh cells), and found a differential gene expression signature in multiple B cell pathways. Most striking was impaired TIGIT expression on MS-derived B cells mediated by dysregulation of the transcription factor TCF4. Activated circulating Tfh cells (cTfh cells) expressed CD155, the ligand of TIGIT, and TIGIT on B cells revealed their capacity to suppress the proliferation of IL-17-producing cTfh cells via TIGIT/CD155 axis. Finally, CCR6+ cTfh cells were significantly increased in MS and their frequency was inversely correlated with that of TIGIT+ B cells. Together, these data suggest that the dysregulation of negative feedback loops between TIGIT+ memory B cells and cTfh cells in MS drive the activated immune system in the disease.
2022-10-19 | GSE211358 | GEO
Project description:Understanding human Regulatory T cell (Treg) heterogeneity may identify markers of disease pathogenesis and facilitate the development of optimized cellular therapeutics. Previous analysis revealed that the co-inhibitory receptor T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) was highly expressed on tTreg. The negative regulator TIGIT and the co-stimulatory factor CD226 bind the common ligand CD155. Human regulatory T cells (CD4+CD25+CD127-/lo) from adult peripheral blood were sub-fractionated based on the markers CD226 and TIGIT and were subsequently expanded in vitro according to clinical expansion protocols. The transcriptional profile of the final cell products uncovered considerable heterogeneity in terms of in vitro expansion and suppressive capacity. Most notably, the CD226+TIGIT- fraction adopted a transcriptional profile most similar to that of conventional T cells, including the capacity for effector cytokine production.
2015-04-30 | GSE62015 | GEO
Project description:The CD155/TIGIT axis can be co-opted during immune evasion in chronic viral infections and cancer. Pancreatic adenocarcinoma (PDAC) is a highly lethal malignancy, and immune-based strategies to combat this disease have been largely unsuccessful to date. We corroborate prior reports that a substantial portion of PDAC harbors predicted high affinity MHC class I-restricted neoepitopes and extend these findings to advanced/metastatic disease. Using two novel preclinical models of neoantigen-expressing PDAC, we demonstrate that intratumoral neoantigen-specific CD8+ T cells adopt multiple states of dysfunction, which are similar to tumor-infiltrating lymphocytes of human PDAC patients. Mechanistically, genetic and/or pharmacologic modulation of the CD155/TIGIT axis was sufficient to promote immune evasion in autochthonous neoantigen-expressing PDAC. Finally, we demonstrate that the CD155/TIGIT axis is critical to maintain immune evasion in PDAC and uncover a combination immunotherapy (TIGIT/PD-1 co-blockade plus CD40 agonism) that elicits profound anti-tumor responses in preclinical models, now poised for clinical evaluation.
2021-07-25 | GSE163059 | GEO
Project description:TIGIT+ Tregs suppress Th1 and Th17 responses while sparing Th2 responses. Analysis of global gene expression of TIGIT+ vs. TIGIT- Tregs from naive mice reveled that TIGIT+ Tregs display an activated phenotype and are enriched for Treg signature genes including the Treg effector molecule Fgl2 which enables them to selectively spare Th2 responses. TIGIT+ and TIGIT- Tregs were sorted from naïve Foxp3-GFP KI mice (pooled spleen and lymph nodes) TIGIT: T cell immunoreceptor with Ig and ITIM domains
2014-12-12 | E-GEOD-56299 | biostudies-arrayexpress
Project description:In this study, we aimed to assess the prognostic value of CD226 on tumor-infiltrating lymphocytes derived from liver metastases of colorectal cancer (CRC) patients treated with chemotherapy and radical surgery. CD226high expression was associated with a potent immune infiltrate in RNAseq from primary colorectal cancer and liver metastases. CD226 expression contributes to defining the immune contexture of CRC liver metastases and primary tumors. In liver metastases, CD226 expression on CD8 T cells was not specifically co-expressed with other immune checkpoints such as PD1, TIGIT and TIM3. Multivariate Cox regression analysis revealed that CD226 expression on CD8 T cells was an independent prognostic factor (p=0.003) along with CD3 density at invasion margins (p=0.003) and TIGIT expression on CD4 T cells (p=0.019). CD155 was not associated with CD226 prognostic value. Gene expression analysis in a validation dataset confirmed the prognostic value of CD226 selectively in liver metastases but not in primary tumors. Down regulation of CD226 on CD8+ infiltrating lymphocytes in liver microenvironment might be restored by IL-15 treatment. CD226 expression on liver metastases-infiltrating CD8+ contributes selectively to the immune surveillance of liver metastases from CRC and displays a prognostic value for patients undergoing radical surgery.
2022-12-01 | GSE207194 | GEO
Project description:Lethally irradiated mice were transferred with bone marrow cells together with allogeneic Treg cells isolated from CD226+/+ TIGIT+/+, CD226-/- TIGIT+/+, CD226+/+ TIGIT-/-, or CD226-/- TIGIT-/- mice, followed by allogeneic wild-type Tconv cells two days later to induce acute GVHD. We performed scRNA sequencing of donor T cells isolated from the spleen of recipient mice eight days after GVHD induction.
2021-05-18 | GSE155250 | GEO
Project description:We recently found that loss of the activating receptor CD226 (DNAM-1) was a critical mechanism affecting CD8+ T cell responsiveness to TCR stimulation. To better understand the molecular differences between CD226- and CD226+ CD8+ T cells, we decided to perform a global transcriptional analysis of purified naive (Tn, CD62L+CD45RA+), central memory (Tcm, CD62L+CD45RA-) and terminal effector memory (Temra, CD62L-CD45RA+) CD226+ and CD226- CD8+ T cells using next generation RNA sequencing.
2020-10-30 | GSE135291 | GEO