Human memory T cells: generation, compartmentalization and homeostasis

Key Points Most of our understanding of memory T cell generation, function and maintenance comes from mouse studies, which cannot recapitulate the exposure to diverse antigens and microbiota that occurs over many decades in humans. Memory T cell frequency dynamically changes throughout the human lifetime and this can be divided into three phases: memory generation, memory homeostasis and immunosenescence. CD45RO + CD45RA − T cells comprise diverse memory T cell subsets, including central memory T (T CM ) cells, effector memory T (T EM ) cells, stem cell memory T (T SCM ) cells and tissue-resident memory T (T RM ) cells, which are heterogeneous in their generation, distribution and function. Memory T cells that are specific for antigens from ubiquitous pathogens and possibly from endogenous flora are generated early in life and are preferentially compartmentalized at the sites of infection throughout adulthood. Human memory T cells in diverse tissue sites are homeostatically maintained, potentially through tonic T cell receptor signalling, and can show extensive cross reactivity and can persist for decades. The induction of memory CD4 + and CD8 + T cells through vaccination can enhance protection against pathogens, and might be improved by considering the anatomical location and the timing of vaccine administration during the early stages of life. Most of our understanding of immunological memory comes from studies in mice. However, these studies cannot recapitulate the exposure to numerous diverse pathogens that occurs over decades in humans. But, as reviewed here, recent studies focusing on human memory T cells are revealing important features of these cells, including subset heterogeneity and spatial compartmentalization. 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.