T cell receptor signalling in the control of regulatory T cell differentiation and function

Abstract

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.

Figure 1. Treg cell differentiation as an alternative agonist antigen-induced cell fate

(a) Following rearrangement of T cell receptors (TCRs), thymocytes undergo selection and maturation processes in the cortex and medulla based on their TCR reactivity. Immature CD4⁺CD8⁺ double-positive (DP) T cells interact with the cortical thymic epithelial cells (cTECs) and bone marrow-derived antigen-presenting cells, such as dendritic cells (DCs). T cells that recognize high affinity self peptide–MHC complexes, designated as high-affinity self antigen, classically undergo apoptosis (that is clonal deletion). High-affinity antigen can also induce DP cells to differentiate to intestinal intraepithelial lymphocytes (IELs). T cells with low-affinity to self peptide–MHC complexes are positively selected and differentiate to CD4⁺ or CD8⁺ single-positive (SP) cells while they migrate from the cortex to the medulla. SP cells continue to sample antigens in the medulla presented by DCs and medullary TECs (mTECs). mTECs express the nuclear factor Aire that promotes the expression of tissue-specific antigens. Stimulation of SP cells by high-affinity self antigen can induce clonal deletion of T cells. Alternatively, strong TCR signals can induce CD4⁺ SP cells to differentiate to thymic Treg (tTreg) cells. (b) Conventional T cells emigrate from the thymus and circulate as a pool of naïve T cells in peripheral lymphoid tissues. Recognition of agonist antigen presented by antigen-presenting cells such as DCs induces distinct T cell fates including clonal deletion as well as differentiation of effector T cells and peripherally derived Treg (pTreg) cells.

Figure 2. tTreg cell fate specification by TCR and accessary signals

(a) CD4 single-positive (SP) thymocytes are educated in the medulla by sampling antigens presented by medullary thymic epithelial cells (mTECs) and bone marrow-derived antigen-presenting cells such as dendritic cells (DCs). Antigen-triggered TCR signaling plays a principal role in dictating the SP cell fates. Weak TCR stimulation promotes the continuous maturation of SP cells into conventional T cells. Transient stimulation of SP cells by high-affinity antigens is likely sufficient to activate the Treg cell-stimulatory signaling pathways including the IκB kinase (IKK) and Ca²⁺, while the activities of Treg cell-inhibitory signaling modules, including CD3ζ and Akt, may not reach an optimal level (signaling threshold, demarcated by the dotted line). Persistent stimulation of SP cells by high-affinity antigens activates Treg cell stimulatory as well as inhibitory signaling pathways, which is not permissive for tTreg cell differentiation, but may trigger T cell clonal deletion. The red dot depicts the level of antigen engagement (duration) and the signaling activity of the indicated modules (strength). (b) Despite a relatively distinct mode of TCR signaling being involved in the control of tTreg cell differentiation and T cell deletion, agonist antigen recognition can induce overlapping T cell fates under certain conditions. Accessory signals provided by co-stimulatory receptors such as CD28 and CD27 as well as cytokines including TGF-β and IL-2 promote tTreg cell differentiation by suppressing T cell clonal deletion.

Figure 3. tTreg cells egressed from the thymus display a resting Treg cell phenotype

tTreg cell differentiation in the medulla is triggered by intermittent TCR signals that, coupled with Foxp3- and CTLA-4-mediated tuning of the TCR signal, promote recent thymic emigrant tTreg cells to exhibit a resting Treg cell phenotype.

Figure 4. Treg cell recirculation and transcriptional control of Treg cell function

(a) Similar to conventional naïve T cells, resting Treg cells circulate between lymph nodes, lymph and blood. Resting Treg cells enter lymph nodes via high endothelial venues (HEVs) present within the paracortical regions. They further migrate to the T cell zone and scan for antigens presented by dendritic cells (DCs) that are recruited from target tissues via the afferent lymphatic. Resting Treg cells that fail to detect high affinity antigens recirculate back to the blood through the efferent lymphatic, whereas agonist antigen-stimulated resting Treg cells differentiate into activated Treg cells, proliferate and enter the circulation. Activated Treg cells migrate to non-lymphoid tissues where they can be re-stimulated, proliferate or undergo apoptosis. Activated Treg cells may leave the tissue via the afferent lymphatic and recirculate through lymph nodes, lymph and blood. (b) Resting Treg cell homeostasis is promoted by the Foxo family of transcription factor Foxo1 that suppresses the inflammatory phenotype of Treg cells and induces the expression of lymphoid organ homing molecules including the chemokine receptor CCR7. Foxo1 and CCR7 are required for Treg cell function, which may be mediated by resting Treg cell-specific suppressive mechanisms. While resting Treg cells experience some level of TCR signaling, they are converted to activated Treg cells following strong antigen stimulation. Multiple TCR-induced signaling pathways, including Ubc13-dependent activation of NF-κB and STIM-dependent activation of NFAT, are crucial for maintaining the Treg cell identity via Foxp3 induction as well as promoting the activated Treg cell-mediated control of immune tolerance and homeostasis. Furthermore, TCR-triggered Foxo1 inactivation supports activated Treg cell trafficking to target tissues for the control of immune tolerance.