Tissue adaptation and clonal segregation of human memory T cells in barrier sites

T lymphocytes migrate to barrier sites after exposure to pathogen-derived antigens to provide localized immune defense and long-term surveillance. However, unique tissue adaptations of barrier T cells and the extent to which they participate in clonal networks remains unclear. In this study, we utilized our organ donor tissue resource to examine T cells in barrier sites (skin, lung, jejunum), their associated lymph nodes, other lymphoid tissues (spleen and bone marrow), and circulation. By integrating multiple single-cell protein and transcript profiling technologies, we demonstrate that human barrier sites contain site-adapted memory T cell populations, including tissue-resident memory T cells (TRM) that exhibit both shared barrier TRM signatures and tissue-specific residency profiles. Additionally, incorporating T cell receptor and RNA-sequencing analysis, we show that lung T cell clones form global networks with clones in lymphoid sites and circulation, and comprise widely disseminated clones of TEM/TEMRA subset that display distinct effector phenotypes; while T cells in skin and jejunum are predominantly TRM and participate primarily in localized clonal networks with tissue-associated lymph nodes but are largely compartmentalized. Overall design: joint single-cell RNA/T cell receptor sequencing