Regulatory T Cell Development in the Thymus

Abstract

Development of a comprehensive regulatory T (T_reg) cell compartment in the thymus is required to maintain immune homeostasis and prevent autoimmunity. In this study, we review cellular and molecular determinants of T_reg cell development in the thymus. We focus on the evidence for a self-antigen-focused T_reg cell repertoire as well as the APCs responsible for presenting self-antigens to developing thymocytes. We also cover the contribution of different cytokines to thymic T_reg development and the cellular populations that produce these cytokines. Finally, we update the originally proposed "two-step" model of thymic T_reg differentiation by incorporating new evidence demonstrating that T_reg cells develop from two T_reg progenitor populations and discuss the functional importance of T_reg cells generated via either progenitor pathway.

Figure 1.

A, Model of thymic T_reg cell development. CD4 single positive thymocytes interact with a range of different affinity for self-antigens presented by thymic APC subsets including, SIRPα⁺ and CD8α⁺ DC, pDC, mTEC, B cells and perhaps macrophages. TCR signal strength initiates fate decisions. Weak TCR signaling is required to develop T_conv, while strong TCR stimulation drives clonal deletion. Intermediate TCR signaling drives T_reg cell commitment; stronger TCR signals lead to upregulation of CD25 generating a CD25⁺ T_regP while weaker TCR stimulation causes upregulation of FOXP3 and produces a FOXP3^lo T_regP. Some CD25⁺ T_regP still undergo clonal deletion, likely due to the high TCR signal strength experienced by this population and FOXP3 expression in FOXP3^lo T_regP drives clonal deletion unless counterbalanced by survival signals mediated by engagement of γC cytokines. When either T_regP bind IL-2, or IL-15, this activates STAT5 and completes the differentiation of mature tT_reg cells, defined by dual expression of CD25 and FOXP3. B, Cytokine producing cells in T_reg cell development. Various cells in the thymus contribute cytokines to the thymic microenvironment. cTEC produce IL-7 which may function as a survival factor for developing thymocytes in the cortex. mTEC have been shown to produce IL-15 as well as low levels of IL-7. mTEC also express CD25 which may function to transpresent IL-2 to developing T_regP or deplete local IL-2 from T_regP. DC derived IL-2 may be produced by CD8α⁺ DC or SIRPα⁺ DC however, SIRPα⁺ DC also express CD25 which may modulate local IL-2 availability. It is unknown if pDC produce T_reg inducing cytokines. Similarly, it is unknown if thymic B cells contribute any cytokines capable of driving T_reg differentiation or serve only as a antigen presenting cell. Tuft cells produce IL-25 which acts on NKT2 cells to produce intrathymic IL-4. IL-4 plays a role in promoting survival and/or differentiation of Foxp3^lo T_regP. Finally, T cells represent the critical source of IL-2 required to drive T_reg cell differentiation, however, it is unclear if the IL-2 is being produced by CD25⁺ T_regP or a subset of recirculating effector T cells.