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TGF-b promotes stem-like T cells via enforcing their lymphoid tissue retention

ABSTRACT: Stem-like CD8+ T cells sustain the antigen-specific CD8+ T cell response during chronic antigen exposure. However, the signals that control the maintenance and differentiation of these cells are largely unknown. Here, we demonstrated that TGF-b was essential for the optimal maintenance of these cells and inhibited their differentiation into migratory effectors during chronic viral infection. Mechanistically, stem-like CD8+ T cells carried a unique expression pattern of a4 integrins (i.e., a4b1hi and a4b7lo) controlled by TGF-b. In the absence of TGF-b signaling, greatly enhanced expression of migration-related markers, including altered expression of a4 integrins led to enhanced egress of stem-like CD8+ T cells into the circulation accompanied by further differentiation into transitional states. Blocking a4 integrin significantly promoted their lymphoid tissue retention and therefore partially rescued the defective maintenance of Tcf-1+ subset in the absence of TGF-b signaling. Thus, TGF-b promotes the maintenance and inhibits the further differentiation of stem-like T cells at least partially via enforcing their lymphoid tissue residency.

ORGANISM(S): Mus musculus

PROVIDER: GSE206646 | GEO | 2022/06/25

REPOSITORIES: GEO

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Project description:Transforming growth factor-Î² (TGF-Î²) has been implicated in the control of differentiation and proliferation of multiple cell types. However, a role for TGF-Î² in the control of immune homeostasis is not fully understood because of its pleiotropic action. Here we report that complete ablation of the TGF-Î² signaling in T cells engendered aggressive early-onset, multiorgan, autoimmune-associated lesions with 100% mortality. Peripheral CD4+ and CD8+ T cells with TGF-Î²-receptor II (TGF-Î²RII) deficiency activated cytolytic and T helper 1 (Th1) differentiation program in a cell-intrinsic T cell receptor (TCR)-specific fashion. Furthermore, TGF-Î²RII deficiency blocked the development of canonical CD1d-restricted NKT cells. Instead, it facilitated generation of a highly pathogenic T cell subset exhibiting multiple hallmarks of NK cells and sharply elevated amounts of FasL, perforin, granzymes, and interferon-Î³. Thus, TGF-Î² signaling in peripheral T cells is crucial in restraining TCR activation-dependent Th1, cytotoxic, and NK cell-like differentiation program which, when left unchecked, leads to rapidly progressing fatal autoimmunity. Experiment Overall Design: To better understand the basis for pathogenicity of TGF-Î²RII-deficient NK1.1+ T cells, we performed gene expression profiling of NK1.1+ and NK1.1â T cell subsets from Tgfbr2fl/fl x CD4-Cre mice. We limited our analysis to CD8+ T cell subsets because NK1.1+ CD8 T cells made up 70% of total NK1.1+ T cells in Tgfbr2fl/fl x CD4-Cre mice, and this T cell subset showed the greatest numerical increase compared to littermate control mice. Thus, in these experiments we used FACS-sorted NK1.1+ and NK1.1â CD8+ T cells from 15- to 17-day-old mutant mice and total CD8+ T cells from Tgfbr2fl/wt x CD4-Cre littermate controls. Experiment Overall Design: mRNA expression profiles of NK1.1+ and NK1.1â CD8+ T cells from Tgfbr2fl/fl x CD4-Cre (KO) mice were compared to NK1.1â T cells from littermate control Tgfbr2fl/WT x CD4-Cre (Control) mice.

Project description:Collombet2016 - Lymphoid and myeloid cell specification and transdifferentiation This model is described in the article: Logical modeling of lymphoid and myeloid cell specification and transdifferentiation Samuel Collombet, Chris van Oevelen, Jose Luis Sardina Ortega, Wassim Abou-Jaoudé, Bruno Di Stefano, Morgane Thomas-Chollier, Thomas Graf, and Denis Thieffry Proceedings of the National Academy of Sciences of the United States of America Abstract: Blood cells are derived from a common set of hematopoietic stem cells, which differentiate into more specific progenitors of the myeloid and lymphoid lineages, ultimately leading to differentiated cells. This developmental process is controlled by a complex regulatory network involving cytokines and their receptors, transcription factors, and chromatin remodelers. Using public data and data from our own molecular genetic experiments (quantitative PCR, Western blot, EMSA) or genome-wide assays (RNA-sequencing, ChIP-sequencing), we have assembled a comprehensive regulatory network encompassing the main transcription factors and signaling components involved in myeloid and lymphoid development. Focusing on B-cell and macrophage development, we defined a qualitative dynamical model recapitulating cytokine-induced differentiation of common progenitors, the effect of various reported gene knockdowns, and the reprogramming of pre-B cells into macrophages induced by the ectopic expression of specific transcription factors. The resulting network model can be used as a template for the integration of new hematopoietic differentiation and transdifferentiation data to foster our understanding of lymphoid/myeloid cell-fate decisions. This model is hosted on BioModels Database and identified by: MODEL1610240000. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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TGF-b promotes stem-like T cells via enforcing their lymphoid tissue retention

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