Fig. 1: Three phases of T_reg cell-mediated immune suppression.

a, In phase 1, regulatory T (T_reg) cells suppress the ability of antigen-presenting cells (APCs) to present antigen to and co-stimulate effector T (T_eff) cells. The T cell receptor (TCR) of a T_reg cell forms a tight immune synapse with the antigen–major histocompatibility complex (MHC) complex displayed on the APC, physically blocking effector T cell access to the same antigen. Additionally, T_reg cell CTLA4 preferentially binds to CD80 and CD86 on the APC, blocking effector T cell access to co-stimulatory signalling through the lower affinity receptor, CD28. Upon retreat from the APC, the T_reg cell removes co-stimulatory proteins and antigen–MHC complexes, thereby further abrogating effector T cell activation. These T_reg cell–APC interactions are thought to occur predominantly in secondary lymphoid organs (such as lymph nodes) but might also occur in tissues. b, In phase 2, T_reg cells release a variety of regulatory cytokines into their microenvironment to suppress inflammation. Most notable are IL-10 and TGFβ, which suppress APCs and promote FOXP3 expression, respectively. TGFβ is cleaved from its latent form into its active form by various mechanisms, notably integrin αvβ8 on T_reg cells. T_reg cells express high levels of CD25, which has a higher affinity for IL-2 than the dimeric IL-2 receptor expressed by conventional T cells. Therefore, T_reg cells behave as an ‘IL-2 sink’, restricting the amount available for conventional T cells. T_reg cells also express the ectonucleotidases CD39 and CD73, which work together to convert ATP to adenosine, which has anti-inflammatory properties. c, In phase 3, T_reg cells mediate ‘infectious tolerance’ by inducing the expansion of existing T_reg cells and/or by converting effector T cells into T_reg cells, establishing a long-lasting tolerogenic balance.