Emerging concepts in tissue-resident T cells: lessons from humans

•Human memory T cells are maintained homeostatically in diverse sites.•Localization of human T cell subsets depends on lineage and differentiation state.•Maintenance of human naïve T cells may also be affected by tissue localization.•Blood contains distinct T cell subsets with higher levels of turnover and activation.

Intensified efforts to promote protective T cell-based immunity in vaccines and immunotherapies have created a compelling need to expand our understanding of human T cell function and maintenance beyond its characterization in peripheral blood. Mouse studies of T cell immunity show that, in response to infection, T cells migrate to diverse sites and persist as tissue-resident memory T cells (TRM), which mediate rapid in situ protection on antigen recall. Here we discuss new approaches to probe human T cell immunity, including novel sampling, that indicate a broad distribution and high frequency of human TRM in multiple sites. These newer findings further implicate anatomic compartmentalization as a generalized mechanism for long-term maintenance of human T cells throughout life.