Humans are exposed to >2,000 microbial species8, of which only a small fraction are pathogenic. It is generally thought that these activated, effector T cell populations contain the precursors of antigen-specific long-lived memory T cells, which persistin vivoas heterogeneous populations in multiple sites, and can coordinate protective immune responses upon pathogen re-exposure. Mouse memory CD8+T cell-mediated protection has been exhibited in the well-characterized lymphocytic choriomeningitis virus (LCMV) contamination model and for additional mouse pathogens (for reviews, see1,2). Memory CD4+T cells can similarly mediate protective immune responses in mice to influenza virus35,Mycobacterium tuberculosis6and parasite7infections. While most of our current understanding of memory T cell generation, function and maintenance is based on results from mouse models, studies in mice cannot recapitulate the exposure to multiple pathogens that occurs in humans over decades. The duration of a mouse memory study is typically several months, with the lifespan of laboratory mice lasting 12 years, which constitutes only a small fraction of the decades-long duration of Tildipirosin immunological memory in humans with an average lifespan of 75 Rabbit polyclonal to ACVR2B years or longer. Additionally, humans are exposed to diverse pathogens through the aerodigestive tract, genital mucosa and skin, which are sites of extensive colonization with >2,000 species of commensal microorganisms8. By contrast, most experimental mice are maintained in highly stringent, pathogen-free conditions, thus limiting the breadth of microbial exposure. Therefore, the generation and maintenance of human memory T cells should be considered within the context of the unique human exposure to pathogenic and non-pathogenic microorganisms, and not only relative to mouse models in controlledin vivosettings. Human T cell studies are generally limited in two respects: first, most studies sample only peripheral blood, though the vast majority of memory T cells reside in tissue sites, including lymphoid tissues, intestines, lungs and skin (see later). Second, most studies on human memory T cells use samples obtained from young- or middle-aged adults, although the majority of memory T cell responses are formed during childhood from primary infections. Recent conceptual and technological breakthroughs, however, are now enabling novel explorations of T cell responses in humans. In this Review, we integrate these new studies with previous findings on T cells from healthy and diseased patients for an analysis of the current knowledge of human memory T cells. We describe recent studies that are beginning to assess how memory is organized in human tissue sites, including their functional capacities and antigen specificities, and discuss their implications for promotingin situimmunity in response to vaccines through targeted therapies. We also discuss the accumulation of memory T cells over a lifetime and how compartmentalization and specificity of memory T cells is usually maintained through homeostasis. == Memory T cell accumulation throughout life == The frequency Tildipirosin of memory T cells undergoes dynamic changes throughout an individuals lifetime that can be divided into three phases: memory generation, memory homeostasis, and immunosenescence (Fig. 1). At birth, all T cells in peripheral blood are nave, and memory T cells develop over time in response to diverse antigen exposure. A dramatic increase in the proportion of circulating memory T cells occurs in the first decade of life, and memory T cells comprise up to 35% of circulating T cells by the end of the second decade9. During this initial memory generation phase, particularly during infancy and early childhood, individuals exhibit the highest susceptibility to pathogens as measured by infectious disease hospitalization rates10. == Physique 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 020). Their levels subsequently plateau and are maintained through homeostasis throughout adulthood (ages 3065), 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 Tildipirosin cells in the blood (red line) over time9,12. In the whole body, which includes the.