T Cell Receptor-Regulated TGF-β 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 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 κB (NF-κB). TGF-β prevented TCR-mediated TβRI downregulation, but this was abrogated by interleukin-6 (IL-6). Mitigation of TCR-mediated TβRI downregulation through overexpression of TβRI in naive and activated T cells rendered T cells less responsive and suppressed autoimmunity. Naive T cells in autoimmune patients exhibited reduced TβRI expression and increased TCR-driven proliferation compared to healthy subjects. Thus, TCR-mediated regulation of TβRI-TGF-β signaling acts as a crucial criterion to determine T cell quiescence and activation.

TGF-β induces ST2 and programs ILC2 development

“…For example, T-cell-specific deletion of TβR2 16 or TβR1 14 resulted in lethal inflammation in mice with similar abnormal phenotype and function of T cells. Although we have shown in our most recently published paper that the expression levels (changes) of TβR1, but not TβR2, reflect TGF-β signaling in T cells, both of them are required for TGF-β signaling 57 . Thus, we used Tgfbr2 deletion in this study.…”

Control of Immunoregulatory Molecules by miRNAs in T Cell Activation

“…TGF-β is expressed in naïve T cells preventing T cell activation until sufficient TCR stimulation downregulates the TGF-β type 1 receptor ( 108 – 110 ). TGF-β induces FOXP3, a key transcription factor that promotes Treg differentiation ( 111 ).…”

Targeting MOG to skin macrophages prevents EAE in macaques through TGFβ-induced peripheral tolerance

“…TGF- β 1 prevents spontaneous activation of naïve CD4+ T cells and the induction of widespread autoimmunity (Gorelik & Flavell, 2000; Tu et al , 2018) in part through induction of peripheral FOXP3+ Treg lymphocytes (Chen et al , 2003). Thus, taking advantage of a sensitive test measuring lymphocyte activation through CD25 and CD134 (OX40) expression shortly after specific-antigen stimulation (Zaunders et al , 2009), we assessed whether the increase in blood TGF β in treated animals was associated with an increase in MOG-specific CD4+CD25+OX40+FOXP3+ T cells.…”

“…Nonetheless, this point to a general homeostatic mechanism allowing naïve T cells priming prior to effector response. In fact, sustained TGF β 1 signaling maintains naïve T cells quiescent and lack of this cytokine signaling in T cells causes widespread autoimmune Th1 response (Gorelik & Flavell, 2000; Tu et al , 2018). Moreover, a fall of plasma TGF β 1 was observed at the start of Guillain-Barré, during MS relapse, in systemic lupus erythematosus or associated to effective immunization routes, suggesting that adaptive (auto)immune response is enabled by antigen presentation and co-stimulation but also by an environment lowering threshold for T cell activation (Bhowmick et al , 2009; Fletcher et al , 2008; Manolova et al , 2013; Rieckmann et al , 1994).…”

“…This suggests that IL8 and TGF β may act in concert to maintain immune homeostasis. Numerous experiments establish the central role of TGF β in preserving immune homeostasis keeping naïve T cells quiescent and inducing their differentiation into regulatory or suppressor lymphocytes or restraining effectors (Selvaraj & Geiger, 2008; Ring et al , 2013; Yamazaki et al , 2008; Tu et al , 2018; Chen et al , 2003). On the contrary IL8 is commonly described as a major pro-inflammatory chemokine (Paul, 2013) , while it has also been implicated in homeostasis of subsets of naïve and regulatory CD4+ T lymphocytes (Crespo et al , 2018; Gibbons et al , 2014; Himmel et al , 2011).…”