Dataset Information

T Cell Receptor-Regulated TGF-? Type I Receptor Expression Determines T Cell Quiescence and Activation.

ABSTRACT: It is unclear how quiescence is enforced in naive T cells, but activation by foreign antigens and self-antigens is allowed, despite the presence of inhibitory signals. We showed that active transforming growth factor ? (TGF-?) signaling was present in naive T cells, and T cell receptor (TCR) engagement reduced TGF-? signaling during T cell activation by downregulating TGF-? type 1 receptor (T?RI) through activation of caspase recruitment domain-containing protein 11 (CARD11) and nuclear factor ?B (NF-?B). TGF-? prevented TCR-mediated T?RI downregulation, but this was abrogated by interleukin-6 (IL-6). Mitigation of TCR-mediated T?RI downregulation through overexpression of T?RI in naive and activated T cells rendered T cells less responsive and suppressed autoimmunity. Naive T cells in autoimmune patients exhibited reduced T?RI expression and increased TCR-driven proliferation compared to healthy subjects. Thus, TCR-mediated regulation of T?RI-TGF-? signaling acts as a crucial criterion to determine T cell quiescence and activation.

SUBMITTER: Tu E

PROVIDER: S-EPMC5911925 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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T Cell Receptor-Regulated TGF-β Type I Receptor Expression Determines T Cell Quiescence and Activation.

Tu Eric E Chia Cheryl P Z CPZ Chen Weiwei W Zhang Dunfang D Park Sang A SA Jin Wenwen W Wang Dandan D Alegre Maria-Luisa ML Zhang Ying E YE Sun Lingyun L Chen WanJun W

Immunity 20180401 4

It is unclear how quiescence is enforced in naive T cells, but activation by foreign antigens and self-antigens is allowed, despite the presence of inhibitory signals. We showed that active transforming growth factor β (TGF-β) signaling was present in naive T cells, and T cell receptor (TCR) engagement reduced TGF-β signaling during T cell activation by downregulating TGF-β type 1 receptor (TβRI) through activation of caspase recruitment domain-containing protein 11 (CARD11) and nuclear factor κ ...[more]

PMID: 29669252

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Project description:Smooth muscle cells (SMCs) play critical roles in a number of diseases; however, the molecular mechanism underlying their development is unclear. Although the role of TGF?1 signaling in SMC development is well established, the downstream molecular signals are not fully understood. We used several rat multipotent adult progenitor cell ((r)MAPC) lines that express levels of Oct4 mRNA similar to hypoblast stem cells (HypoSC), and can differentiate robustly to mesodermal and endodermal cell types. TGF?1 alone, or with PDGF-BB, induces differentiation of rMAPCs to SMCs, which expressed structural SMC proteins, including ?-smooth muscle actin (?SMA), and contribute to the SMC coat of blood vessels in vivo. A genome-wide time-course transcriptome analysis revealed that transcripts of Baf60c, part of the SWI/SNF actin binding chromatin remodeling complex D-3 (SMARCD3/BAF60c), were significantly induced during MAPC-SMC differentiation. We demonstrated that BAF60c is a necessary co-regulator of TGF?1 mediated induction of SMC genes. Knock-down of Baf60c decreased SMC gene expression in rMAPCs whereas ectopic expression of Baf60c was sufficient to commit rMAPCs to SMCs in the absence of exogenous cytokines. TGF?1 activates Baf60c via the direct binding of SMAD2/3 complexes to the Baf60c promoter region. Chromatin- and co-immunoprecipitation studies demonstrated that regulation of SMC genes by BAF60c is mediated via interaction with SRF binding CArG box-containing promoter elements in SMC genes. We noted that compared with TGF?1, Baf60c overexpression in rMAPC yielded SMC with a more immature phenotype. Similarly, Baf60c induced an immature phenotype in rat aortic SMCs marked by increased cell proliferation and decreased contractile marker expression. Thus, Baf60c is important for TGF?-mediated commitment of primitive stem cells (rMAPCs) to SMCs and is associated with induction of a proliferative state of quiescent SMCs. The MAPC-SMC differentiation system may be useful for identification of additional critical (co-)regulators of SMC development.

Dataset Information

T Cell Receptor-Regulated TGF-? Type I Receptor Expression Determines T Cell Quiescence and Activation.

Publications

T Cell Receptor-Regulated TGF-β Type I Receptor Expression Determines T Cell Quiescence and Activation.

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