Homeostatic control of regulatory T cell diversity

Key Points Regulatory T (T Reg ) cells can be induced in both the thymus and the periphery. Together, these T Reg cells constitute the peripheral T Reg cell pool, which can be divided into 'central' T Reg cells, 'effector' T Reg cells and 'tissue-resident' T Reg cells. Effector T Reg cells show plasticity and heterogeneity, with distinct phenotypic and functional profiles being induced in response to different microenvironments. Non-lymphoid tissues contain T Reg cells. This population is likely to be a heterogeneous mixture of transiently migrating effector T Reg cells and long-term resident T Reg cells with additional local functions. T Reg cell homeostasis is a dynamic process, with a stable population size being maintained through a balance of proliferation and apoptosis. The predominant central T Reg cell population size is modulated by pro-apoptotic changes (forkhead box P3 (FOXP3)-mediated phosphorylation of B-cell lymphoma 2-interacting mediator of cell death (BIM)) and pro-survival responses (interleukin-2 (IL-2)-mediated upregulation of induced myeloid cell leukaemia 1 (MCL1)). Subpopulations of T Reg cells can have distinct molecular pathways of homeostasis. T Reg cell and conventional T cell subsets can act in competition with each other for limiting IL-2 and other homeostatic mediators. Dysregulation of T Reg cell homeostasis through competition can result in immune-mediated disease, including graft-versus-host disease. Regulatory T (T Reg ) cells are crucial for maintaining immune homeostasis in the body, with recent data showing that distinct T Reg cell subsets become specialized to function in different tissues. Here, Liston and Gray highlight the need to regulate the number and function of the T Reg cells themselves, and they describe the dynamic processes that achieve this homeostasis and functional specialization of T Reg cell subsets. Regulatory T (T Reg ) cells constitute an essential counterbalance to adaptive immune responses. Failure to maintain appropriate T Reg cell numbers or function leads to autoimmune, malignant and immunodeficient conditions. Dynamic homeostatic processes preserve the number of forkhead box P3-expressing (FOXP3 + ) T Reg cells within a healthy range, with high rates of cell division being offset by apoptosis under steady-state conditions. Recent studies have shown that T Reg cells become specialized for different environmental contexts, tailoring their functions and homeostatic properties to a wide range of t