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

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.