Regulatory T cells (TReg cells), a specialized T cell lineage, have a pivotal function in the control of self tolerance and inflammatory responses. Recent studies have revealed a discrete mode of T cell receptor (TCR) signalling that regulates TReg cell differentiation, maintenance and function and that affects gene expression, metabolism, cell adhesion and migration of these cells. Here, we discuss the emerging understanding of TCR-guided differentiation of TReg cells in the context of their function in health and disease.
At a glance
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This study shows that the TCR-induced immediate early genes encoding the NR4A nuclear receptor family members are crucial for Foxp3 expression, which implies that TReg cell differentiation is promoted by transcriptional factors activated downstream of TCR signalling.
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References 98 and 99 report that during TReg cell lineage commitment, FOXP3 expression is preceded by the TCR-dependent establishment of key regulatory elements and changes in DNA methylation at several genomic loci. These changes prepare precursor cells for FOXP3 expression and its essential function in regulating gene expression in TReg cells.
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This study demonstrates that activated TReg cell differentiation is associated with the repression of FOXO1-dependent gene transcription, concomitant with AKT-induced FOXO1 phosphorylation. FOXO1 inactivation is essential for the migration of activated TReg cells to target tissues and the suppression of CD8+ T cell-dependent autoimmunity and tumour immunity.
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References 116 and 117 demonstrate that TCR expression in mature TReg cells is dispensable for maintaining the expression of FOXP3 and the TReg cell-specific epigenome but is required for the suppressor capacity of TReg cells.
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References 118 and 119 reveal that the hypomethylated intronic Foxp3 regulatory element CNS2 has an essential function in controlling the TReg cell identity in antigen-experienced TReg cells. CNS2 contains cis regulatory motifs that sense cytokine and TCR signals.
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This study shows that TReg cells have elevated steady-state mTORC1 activity. mTORC1 deficiency results in compromised TReg cell function, which is partly due to enhanced mTORC2 signalling and is further associated with defective lipid metabolism.
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This study reports that TReg cell differentiation is associated with attenuated AKT-triggered FOXO1 nuclear exclusion. FOXO1 controls a gene expression programme that is distinct from that of FOXP3 and is indispensable for TReg cell function.
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This study reports that TReg cells expressing phosphorylated STAT5 exist in clusters with conventional IL-2+ T cells in secondary lymphoid tissues, and such colocalization is dependent on TReg cell expression of TCR. These findings imply a negative feedback mechanism that promotes tolerance control of autoreactive T cells.
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This study reports that TReg cells that are reactive to a prostate-associated self antigen are highly enriched in oncogene-induced prostate tumours. Differentiation of these TReg cells in the thymus is determined by AIRE-dependent expression of prostate tissue antigens by mTECs.
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References 136 and 137 show that maternal TReg cells specific for fetal antigens are induced during pregnancy. pTReg cell differentiation is dependent on the Foxp3 intronic regulatory element CNS1 that has emerged in placental mammals during evolution. Furthermore, TReg cells persist post-partum and rapidly expand during subsequent pregnancies. The robust recall (memory) TReg cell response promotes immune tolerance to the fetus.
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This study reports that exposure to maternal tissues induces TReg cell differentiation and stable immune tolerance to non-inherited maternal antigens in female offspring. Such female offspring experience reduced fatal wasting when mated with males that share these antigens.
- Peripheral education of the immune system by colonic commensal microbiota. Nature 478, 250–254 (2011).
This study reports that colonic TReg cells express distinct TCRs, many of which react to antigens derived from commensal bacteria. These TCRs, when expressed in precursor cells, do not facilitate tTReg cell development but promote microbiota-dependent pTReg cell differentiation.
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- Smad3 binding to the foxp3 enhancer is dispensable for the development of regulatory T cells with the exception of the gut. J. Exp. Med. 209, 1529–1535 (2012). , , , &
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- Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma. J. Exp. Med. 210, 1695–1710 (2013). et al.
- Activating Fcγ receptors contribute to the antitumor activities of immunoregulatory receptor-targeting antibodies. J. Exp. Med. 210, 1685–1693 (2013). et al.
- Anti-CTLA-4 antibodies of IgG2a isotype enhance antitumor activity through reduction of intratumoral regulatory T cells. Cancer Immunol. Res. 1, 32–42 (2013). et al.