Origins of CD4+ circulating and tissue-resident memory T-cells

Abstract

In response to infection, naive CD4⁺ T-cells proliferate and differentiate into several possible effector subsets, including conventional T helper effector cells (T_H 1, T_H 2, T_H 17), T regulatory cells (T_reg ) and T follicular helper cells (T_FH ). Once infection is cleared, a small population of long-lived memory cells remains that mediate immune defenses against reinfection. Memory T lymphocytes have classically been categorized into central memory cell (T_CM ) and effector memory cell (T_EM ) subsets, both of which circulate between blood, secondary lymphoid organs and in some cases non-lymphoid tissues. A third subset of memory cells, referred to as tissue-resident memory cells (T_RM ), resides in tissues without recirculation, serving as 'first line' of defense at barrier sites, such as skin, lung and intestinal mucosa, and augmenting innate immunity in the earliest phases of reinfection and recruiting circulating CD4⁺ and CD8⁺ T-cells. The presence of multiple CD4⁺ T helper subsets has complicated studies of CD4⁺ memory T-cell differentiation, and the mediators required to support their function. In this review, we summarize recent investigations into the origins of CD4⁺ memory T-cell populations and discuss studies addressing CD4⁺ T_RM differentiation in barrier tissues.

Keywords: T helper; protective immunity.

Figure 1

Models of CD4⁺ memory T‐cell formation. (a) Upon antigen encounter, naive CD4⁺ T‐cells differentiate into effector subsets based on the type of infection. Within each effector CD4⁺ subset, there potentially exist terminal effectors (TE) and memory precursor (MP) effectors. The majority of TEs die during the contraction, while MPs can survive and transition into resting memory cells. CD4⁺ tissue‐resident memory cells (T_RM) may differentiate from: (1) the naive subset; (2) MP cells within the effector population; or (3) committed memory cells. (b) Two models for T follicular helper cell (T_FH) multi‐potency: (1) T_FH memory cells retain cellular plasticity and can differentiate into T_H1 or T_FH secondary effectors based on signals present during secondary challenge; (2) T_FH memory cells are actually a heterogeneous population with subsets that are biased or primed towards a particular secondary effector lineage (T_H1 or T_FH).

Figure 2

Following infection, CD4⁺ tissue‐resident memory cells (T_RM) are recruited to tissues from circulation and secondary lymphoid organs (SLOs). The majority of CD4⁺  T_RM express high levels of CD69 and can form clusters with other resident immune subsets, including CD8⁺ TRM, macrophages and antiegn‐presenting cells (APCs). Cytokine signalling may also play a role in recruitment and retention, although specific cytokines are preferred by each tissue.