The roles of resident, central and effector memory CD4 T‐cells in protective immunity following infection or vaccination

Abstract

SummaryImmunological memory provides rapid protection to pathogens previously encountered through infection or vaccination. CD4 T‐cells play a central role in all adaptive immune responses. Vaccines must, therefore, activate CD4 T‐cells if they are to generate protective immunity. For many diseases, we do not have effective vaccines. These include human immunodeficiency virus (HIV), tuberculosis and malaria, which are responsible for many millions of deaths each year across the globe. CD4 T‐cells play many different roles during the immune response coordinating the actions of many other cells. In order to harness the diverse protective effects of memory CD4 T‐cells, we need to understand how memory CD4 T‐cells are generated and how they protect the host. Here we review recent findings on the location of different subsets of memory CD4 T‐cells that are found in peripheral tissues (tissue resident memory T‐cells) and in the circulation (central and effector memory T‐cells). We discuss the generation of these cells, and the evidence that demonstrates how they provide immune protection in animal and human challenge models.

Knowns and unknowns of tissue‐resident memory T cells

“…One of several confounders is that T resident memory (TRM) cells of mice and humans are similar, but only up to a point. [2][3][4] Furthermore, there appears to be far greater heterogeneity among CD4 than CD8 TRM. Considerable illumination came with a paper from Donna Farber's laboratory, characterizing TRM cells from distinct tissues of humans and mice.…”

“…Interestingly, the bulk of this core signature is shared between TRM from different tissues, with only a small subset defining the difference between, for example, spleen versus lung. A number of recent papers have considered features of the tissue‐resident populations at different sites, including lung, adipose tissue and brain, noting that not only TRM cells, but also Tregs, macrophages and dendritic cells show tissue‐specific, resident, phenotypes …”

“…There is much still to be learnt about the anatomical localization and connectivity of tissue‐resident immune populations. MacLeod and colleagues have speculated that clustering of TRM cells with APC and B cells may be a step on the way to formation of the ectopic lymphoid follicles that often mark out inflammatory tissues . An important new review of TRM cells from Goldrath and colleagues considers similarities and differences between CD4 and CD8 TRM functions at different tissue sites .…”

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

“…). Similar to their CD8 + T‐cell counterparts, CD4 + T RM have been shown to facilitate rapid immune defense upon re‐exposure to antigen and can supplant innate immunity in recognizing and responding to recurrent infections . However, much remains to be explored about the phenotype, function and maintenance of CD4 + T RM during infections.…”

“…Similar to their CD8 + T-cell counterparts, CD4 + T RM have been shown to facilitate rapid immune defense upon re-exposure to antigen and can supplant innate immunity in recognizing and responding to recurrent infections. 67 However, much remains to be explored about the phenotype, function and maintenance of CD4 + T RM during infections. Additionally, differences exist between CD4 + and CD8 + T RM in tissue localization, surface marker expression and cytokine cues driving T RM formation; these outstanding questions in the field must be addressed to better define the identity and differentiation of CD4 + T RM .…”