Area under immunosurveillance: dedicated roles of memory CD8 T-cell subsets

Immunological memory, defined as the ability to respond in an enhanced manner upon secondary encounter with the same pathogen, can provide substantial protection against infectious disease. The improved protection is mediated in part by different populations of memory CD8 T cells that are retained after primary infection. Memory cells persist in the absence of pathogen-derived antigens and enable secondary CD8 T-cell responses with accelerated kinetics and of larger magnitude after reencounter with the same pathogen. At least three subsets of memory T cells have been defined that are referred to as central memory CD8 T cells (Tcm), effector memory CD8 T cells (Tem), and tissue-resident memory CD8 T cells (Trm). Tcm and Tem are circulating memory T cells that mediate bodywide immune surveillance in search of invading pathogens. In contrast, Trm permanently reside in peripheral barrier tissues, where they form a stationary defensive line of sentinels that alert the immune system upon pathogen reencounter. The characterization of these different subsets has been instrumental in our understanding of the strategies that memory T cells employ to counter invading pathogens. It is clear that memory T cells not only have a numerical advantage over naive T cells resulting in improved protection in secondary responses, but also acquire distinct sets of competencies that assist in pathogen clearance. Nevertheless, inherent challenges are associated with the allocation of memory T cells to a limited number of subsets. The classification of memory T cells into Tcm, Tem, and Trm may not take into account the full extent of the heterogeneity that is observed in the memory population. Therefore, in this review, we will revisit the current classification of memory subsets, elaborate on functional and migratory properties attributed to Tcm, Tem, and Trm, and discuss how potential heterogeneity within these populations arises and persists.