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

Journal name:
Nature Reviews Immunology
Year published:
Published online


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


  1. TReg cell differentiation as an alternative agonist antigen-induced cell fate.
    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 of the thymus on the basis of their TCR reactivity. Immature CD4CD8 double-positive (DP) T cells interact with 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 self antigen can also induce DP cells to differentiate into intestinal intraepithelial lymphocytes (IELs). T cells with low affinity for self peptide–MHC complexes are positively selected and differentiate into CD4 or CD8 single-positive (SP) cells as 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 autoimmune regulator (AIRE), which 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 into thymus-derived regulatory T (tTReg) cells. b | Conventional T cells emigrate from the thymus and circulate as a pool of naive T cells in peripheral lymphoid tissues. Recognition of agonist antigen that is 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.

  2. A model of tTReg cell fate specification by TCR and accessory signals.
    Figure 2: A model of tTReg cell fate specification by TCR and accessory 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 T cell receptor (TCR) signalling has 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 probably sufficient to activate the regulatory T (TReg) cell-stimulatory signalling pathways, including IκB kinase (IKK) and Ca2+, whereas the activities of TReg cell-inhibitory signalling modules, including CD3ζ and AKT, may not reach an optimal level (signalling threshold demarcated by the dashed line). Persistent stimulation of SP cells by high-affinity antigens activates both TReg cell stimulatory and inhibitory signalling pathways, which is not permissive for thymus-derived TReg (tTReg) cell differentiation but may trigger T cell clonal deletion. The red dot depicts the level of antigen engagement (duration) and the signalling activity of the indicated modules (strength). b | Despite a relatively distinct mode of TCR signalling being involved in the control of tTReg cell differentiation and T cell deletion, the recognition of agonist antigen can induce overlapping T cell fates under certain conditions. Accessory signals that are provided by co-stimulatory receptors such as CD27 and CD28, as well as cytokines, including transforming growth factor-β (TGFβ) and interleukin-2 (IL-2), promote tTReg cell differentiation by suppressing T cell clonal deletion.

  3. tTReg cells that have egressed from the thymus display a resting TReg cell phenotype.
    Figure 3: tTReg cells that have egressed from the thymus display a resting TReg cell phenotype.

    Thymus-derived regulatory T (tTReg) cell differentiation in the medulla is triggered by intermittent T cell receptor (TCR) signals that, coupled with forkhead box P3 (FOXP3)- and cytotoxic T lymphocyte antigen 4 (CTLA4)-mediated tuning of the TCR signal, promote recent thymic emigrant tTReg cells to exhibit a resting TReg cell phenotype. SP cell, single-positive cell.

  4. TReg cell recirculation and transcriptional control of TReg cell function.
    Figure 4: TReg cell recirculation and transcriptional control of TReg cell function.

    a | Similar to conventional naive T cells, resting regulatory T (TReg) cells circulate between lymph nodes, lymph and blood. Resting TReg cells enter lymph nodes via high endothelial venules (HEVs) that are present in the paracortical regions (step 1). 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 vessels. Resting TReg cells that fail to detect high-affinity antigens recirculate back to the blood through the efferent lymphatic vessels, whereas agonist antigen-stimulated resting TReg cells differentiate into activated TReg cells, proliferate and enter the circulation (step 2). Activated TReg cells migrate to non-lymphoid tissues (step 3), where they can be restimulated, proliferate or undergo apoptosis. Activated TReg cells may leave the tissue via the afferent lymphatic vessels (step 4) and recirculate through lymph nodes, lymph and blood. b | Resting TReg cell homeostasis is promoted by the transcription factor forkhead box O1 (FOXO1), which suppresses the inflammatory phenotype of TReg cells and induces the expression of lymphoid organ-homing molecules, including CC-chemokine receptor 7 (CCR7). FOXO1 and CCR7 are required for TReg cell function, which may be mediated by resting TReg cell-specific regulatory (suppressive) mechanisms. Although resting TReg cells experience some level of T cell receptor (TCR) signalling, they convert into activated TReg cells following strong antigen stimulation. Several TCR-induced signalling pathways, including UBC13-dependent activation of nuclear factor-κB (NF-κB) and stromal interaction molecule (STIM)-dependent activation of nuclear factor of activated T cells (NFAT), are crucial for maintaining TReg cell identity through FOXP3 induction, as well as by 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.


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  1. Immunology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.

    • Ming O. Li
  2. Immunology Program, Howard Hughes Medical Institute and Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.

    • Alexander Y. Rudensky

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  • Ming O. Li

    Ming O. Li is a member of the Immunology Program at the Memorial Sloan Kettering Cancer Center (MSKCC), New York, USA, and a professor at Weill Cornell Medical School, New York, USA. He is an international leader in the fields of immune regulation and tumour immunology, in which he has made seminal contributions in defining the regulatory mechanisms of T cell development, homeostasis, tolerance and memory, as well as in elucidating the nature of tumour-elicited innate and adaptive immune responses. He is a Rita Allen Foundation Scholar and is the recipient of the Louise and Allston Boyer Award in Basic Research and, more recently, the AAI-BD Bioscience Investigator Award. Ming O. Li's homepage.

  • Alexander Y. Rudensky

    Alexander Y. Rudensky is the Chairman of the Immunology Program and Director of the Ludwig Center for Cancer Immunotherapy at the Memorial Sloan Kettering Cancer Center (MSKCC), New York, USA, an investigator with the Howard Hughes Medical Institute, and a tri-institutional professor at MSKCC, the Rockefeller University, New York, USA, and Cornell University, Ithaca, New York, USA. He is an internationally recognized leader in the field of immune regulation, in which he has made numerous seminal discoveries, including the identification of the molecular mechanisms of regulatory T cell differentiation. He was elected to the National Academy of Sciences, in 2012, and to the American Academy of Sciences and the National Academy of Medicine, in 2015. He is the recipient of the Searle Scholar Award and, more recently, the Coley Award for Basic Science.

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