Human memory T cells: generation, compartmentalization and homeostasis

Abstract

Memory T cells constitute the most abundant lymphocyte population in the body for the majority of a person's lifetime; however, our understanding of memory T cell generation, function and maintenance mainly derives from mouse studies, which cannot recapitulate the exposure to multiple pathogens that occurs over many decades in humans. In this Review, we discuss studies focused on human memory T cells that reveal key properties of these cells, including subset heterogeneity and diverse tissue residence in multiple mucosal and lymphoid tissue sites. We also review how the function and the adaptability of human memory T cells depend on spatial and temporal compartmentalization.

Figure 1. Memory T cell frequency, pathogen susceptibility and mortality throughout human life

Memory T cells pass through three distinct phases: memory generation, memory homeostasis and immunosenescence. Memory T cells are mostly generated following antigen exposure during infancy, youth and young adulthood (ages 0–20). Their levels subsequently plateau and are maintained through homeostasis throughout adulthood (ages 30–65), after which they enter the third stage and exhibit senescent changes (ages 65 and up). Previous studies have shown that there is an increase in the frequency of memory T cells in the blood (red line) over time^,. In the whole body, which includes the blood, intestines, lungs, skin, liver, brain and lymphoid tissues, the overall frequency of memory T cells (black line) also increases with age. The increase in memory T cell frequency throughout the body inversely correlates to a decrease pathogen susceptibility (dashed line) calculated from infectious disease hospitalization rates (per 10,000 people) recorded from 1998–2006 in the US based on 40,085,978 total hospitalizations.

Figure 2. Model for the generation of human memory T cell subsets

A schematic model for differentiation of circulating and tissue-resident memory T cell subsets. Progressive differentiation of the three major circulating subsets — stem cell memory T cells (T_SCM cells), central memory T cells (T_CM cells) and effector memory T cells (T_EM cells) — from activated naïve T cells is shown relative to the extent of antigen exposure. Effector T cells (T_Eff cells) represent terminally differentiated cells, and death is one outcome of increased antigen exposure and proliferation. Naïve, T_SCM and T_CM cells circulate and migrate to lymphoid tissue, whereas T_EM and T_Eff cells are the subsets with the capacity to traffic to peripheral tissues. Tissueresident memory T cells (T_RM cells) in peripheral tissue sites may derive from either T_EM or T_Eff cells that migrate to these sites via tissue-specific influences. It is possible that T_CM cells could develop into T_RM cells in lymphoid sites (dotted line). T_RM cells in peripheral compartments are likely terminally differentiated since they do not circulate or convert to other memory T cell subsets.

Figure 3. Schematic of memory T cell heterogeneity in peripheral blood and tissues

A Diagram shows the tissue distribution and migration patterns of the major human memory T cell subsets, including three major circulating populations —, stem cell memory T cells (T_SCM cells), central memory T cells (T_CM cells) and effector memory T cells (T_EM cells) — and T_RM cells in multiple sites, as well as CD8⁺ T_RM cells that are defined by expression of CD103 and are associated with mucosal sites and skin. The individual sites are defined in terms of circulation (red), lymphoid origin (grey) or peripheral tissues (yellow). Circulating T_SCM, T_CM and T_EM cell subsets migrate from the blood and circulate through the spleen and lungs, where they can be primed to migrate to intestines. They also migrate via the lymphatics and efferent vessels to lymph nodes. T_RM cells predominate in skin, lungs, bone marrow and intestines, but may also be present within the CD69⁺T_EM subsets in the spleen and lymph nodes. Mucosal sites and the skin also contain specific CD103⁺ T_RM cells. The expression of certain chemokine receptors and/or integrins is associated with T cell migration and/or residence in lymph nodes (CCR7), skin (CCR4, CLA and CCR10), intestines (CCR9 and integrin α4β7), lungs (CCR6) and bone marrow (integrin α2β1). B Key phenotypic and functional properties of circulating and resident subsets are shown, with CD45RA and CCR7 distinguishing circulating memory T cell subsets and CD69 (and CD103) expression delineating T_RM cells from circulating subsets. Memory subsets can produce similar types of recall cytokines, such as interleukin-2 (IL-2), interferon-γ (IFNγ) and tumour necrosis factor (TNF), but differ in the extent and quality of these responses.

Figure 4. Model for compartmentalization of antigen-specific memory T cell subsets in space and time

This schematic shows the relative naïve and memory T cell subset frequencies in the circulation and peripheral sites and at different life stages. The schematic also shows the biased specificity for microbial antigens derived from pathogens that has been observed in specific tissue sites, including cytomegalovirus (CMV) in the blood; Epstein-Barr virus (EBV) in the spleen; vaccinia virus in lymph nodes; influenza virus in the lungs; rotavirus in the intestine and herpes simplex virus (HSV) and varicella zoster virus (VZV) in the skin. In addition, the specificities of some memory T cells at mucosal sites (lungs, intestine and skin) are biased for antigens from the microflora. The relative frequencies of each T cell subset in each tissue site for youths through adults are compiled from Ref. 11, and are extrapolated for infants based on Refs. , . At birth, there is a preponderance of naïve T cells in the circulation, and an abundance of mucosal microbial antigens are encountered during infancy, resulting in seeding of mucosal sites with T_EM cells specific for mucosal pathogens, which could develop into T_RM cells in situ. Infant skin has few, if any T cells (R. Clark, personal communication) and therefore estimates for memory T cell content in skin begin during youth. During childhood, exposure to the ubiquitous pathogenic and non-pathogenic microbial species in each site occurs and new memory T cells are formed which are partitioned as T_RM cells in skin and mucosal sites, and as T_CM cells in lymphoid tissues. This basic partitioning of antigen-specific memory T cell subsets in tissues is maintained during adulthood, with more T_EM and T_CM cell subsets gradually accumulating in the circulation and lymph nodes that could potentially replenish and/or convert to T_RM cells that are lost through attrition.