A non-lymphoid origin for lymph node resident memory T cells

Immunosurveillance of secondary lymphoid organs (SLO) is performed by central memory T cells that recirculate through blood. Resident memory T cells (TRM) remain parked in nonlymphoid tissues and often stably express CD69. We recently identified TRM within SLO, and this study addresses knowledge gaps in their origin and phenotype. Parabiosis of ‘dirty’ mice revealed that CD69 expression is insufficient to infer stable residence. Using selective depletion strategies, parabiosis, imaging, tissue grafting, and photoactivatable T cells, we report that restimulation of TRM within the skin or mucosa results in a substantial increase in TRM that patrol all regions of draining lymph nodes. SLO TRM were derived from nonlymphoid tissue residents. Transcriptional profiling and flow cytometry revealed a refined phenotype shared between both nonlymphoid and SLO TRM. These data demonstrate the nonlymphoid origin of SLO TRM and suggest vaccination strategies by which memory CD8 T cell immunosurveillance can be regionalized to specific lymph nodes. A total of 3 cell populations were analyzed, with 3 replicates per population. Total RNA was isolated from FACS-sorted memory CD8+ memory P14 T cells >30 days after LCMV armstrong infection. Sorted populations include splenic CD62Lhi CD69lo TCM cells, splenic CD62Llo CD69hi TRM cells, and CD62Llo CD69hi CD103lo FRT TRM cells.