Mechanisms of tissue compartmentalization in human T cells

Mechanisms for human memory T cell differentiation and maintenance have predominantly been inferred from studies of peripheral blood, though the majority of T cells reside in lymphoid and non-lymphoid sites. Studies in mice have shown that memory T cells in non-lymphoid sites provide superior protection to pathogens compared to those in blood, defining a subset known as tissue-resident memory T cells (TRM), with emerging roles in lymphoid sites. There are many key unknown aspects of TRM biology in human tissues including if TRM have superior functional abilities, the mechanisms for maintenance of TRM in lymphoid and non-lymphoid sites, and the relatedness of tissue and blood localized T cell subsets. Through a collaboration with the local organ procurement agency, we obtained samples from >15 tissue sites from healthy organ donors of all ages. We analyzed CD8+ T cells in diverse sites and found the majority of TRM cells in lymph nodes (LNs) display an increased proliferative capacity, increased expression of TCF-1, and decreased turnover compared to TRM and effector memory (TEM) cells in other sites including blood, bone marrow (BM), spleen and lung. Further, we identified that exposure to type 1 interferons results in increased downregulation of TCF-1 expression during cell divisions driven by T cell receptor (TCR) stimulation. We investigated the relatedness of CD4+ and CD8+ T cell subsets, including central memory (TCM), effector memory (TEM), TRM, and terminal effectors (TEMRA) by sequencing TCR rearrangements. From diversity analysis of TCR repertoires we found that effector and memory subsets are maintained in a hierarchy from most to least diverse (TCM > TEM and TRM > TEMRA) that is largely conserved across tissues and CD4+ and CD8+ T cell lineages. Overlap analysis revealed the low and high relatedness of TCM and TEMRA cells respectively and this was highly conserved across tissues; in contrast, we found the relatedness of TEM and TRM was more dynamic across tissues. Together, these findings have implications for immune monitoring and modulation, highlighting that lymph nodes may function as reservoirs for long-lived memory T cells with high functional capacity; additionally, we identify cell extrinsic signals that regulate tissue-specific maintenance of T cell memory in lymph node sites.