Regulatory T cell memory

Abstract

Memory for antigen is a defining feature of adaptive immunity. Antigen-specific lymphocyte populations show an increase in number and function after antigen encounter and more rapidly re-expand upon subsequent antigen exposure. Studies of immune memory have primarily focused on effector B cells and T cells with microbial specificity, using prime-challenge models of infection. However, recent work has also identified persistently expanded populations of antigen-specific regulatory T cells that protect against aberrant immune responses. In this Review, we consider the parallels between memory effector T cells and memory regulatory T cells, along with the functional implications of regulatory memory in autoimmunity, antimicrobial host defence and maternal-fetal tolerance. In addition, we discuss emerging evidence for regulatory T cell memory in humans and key unanswered questions in this rapidly evolving field.

Figure 1. Life cycle of regulatory and conventional CD4⁺ T cells

Naive conventional CD4⁺ T cells and regulatory T (T_Reg) cells are generated in the thymus. Upon antigen-specific activation in secondary lymphoid organs, these populations give rise to conventional effector T cells and ‘effector’ T_Reg cells. Effector T_Reg cells can arise from both thymus-derived and peripherally derived T_Reg cells. Central memory T cells are generated from a subset of activated conventional effector T cells and remain in secondary lymphoid organs. It is currently unknown whether central memory T_Reg cells are generated. Effector memory cells are generated from a subset of both conventional T cells and T_Reg cells. These cells migrate to antigen-expressing peripheral tissues where they stably reside (as tissue-resident memory T cells) or where they recirculate between blood and non-lymphoid tissues (as effector memory T cells). It is currently unknown whether the memory T_Reg cell populations that are found in peripheral tissues comprise tissue-resident memory T_Reg cells, effector memory T_Reg cells or both of these subsets. APC, antigen-presenting cell; FOXP3, forkhead box P3; TCR, T cell receptor.

Figure 2. Mouse models for studying memory T_Reg cells

Three primary mouse models have been used to identify and to characterize memory regulatory T (T_Reg) cells. a. In a tissue-specific inducible antigen model, expression of a pseudo-self antigen can be precisely turned on and off. This system facilitates the generation of memory T_Reg cells (by turning on the antigen) and their isolation and characterization in both secondary lymphoid organs and peripheral tissues after the antigen is turned off^,. b. In an antigen-specific gestational model, maternal CD4⁺ T cells with surrogate fetal specificity can be precisely identified during primary pregnancy, post-partum and with fetal antigen restimulation in subsequent pregnancies. c. In an acute infection model with influenza virus, the initial infection is rapidly cleared but virus-specific memory T_Reg cells are generated and maintained long term. These memory T_Reg cells mitigate the tissue damage that occurs upon reinfection with the virus^,.

Figure 3. Predicted model for the relationship between resting, effector and memory T_Reg cells

Regulatory T (T_Reg) cells that are derived in the thymus are maintained in the periphery in a resting or naive state. They are intermittently exposed to their cognate antigens but these T cell receptor MHC interactions are below the threshold for full activation. Upon strong stimulation with antigen in secondary lymphoid organs, resting T _Reg cells are activated, proliferate and differentiate into effector T_Reg cells. A subset of effector T_Reg cells is capable of differentiating into long-lived memory T_Reg cells. Memory T_Reg cells can reside in non-lymphoid tissues and are capable of surviving in the absence of antigen or low levels of intermittent antigen exposure. The figure highlights key features of each population^,,,,,,. IL-2, interleukin-2.