Protective function and durability of mouse lymph node-resident memory CD8 T cells.

Protective lung tissue-resident memory CD8T cells (Trm) form after influenza A virus (IAV) infection. We show that IAV infection of mice generates CD69CD103and other memory CD8T cell populations in lung-draining mediastinal lymph nodes (mLNs) from circulating naive or memory CD8T cells. Repeated antigen exposure, mimicking seasonal IAV infections, generates quaternary memory (4M) CD8T cells that protect mLN from viral infection better than 1M CD8T cells. Better protection by 4M CD8T cells associates with enhanced granzyme A/B expression and stable maintenance of mLN CD69CD1034M CD8T cells, vs the steady decline of CD69CD1031M CD8T cells, paralleling the durability of protective CD69CD1034M vs 1M in the lung after IAV infection. Coordinated upregulation in canonical Trm-associated genes occurs in circulating 4M vs 1M populations without the enrichment of canonical downregulated Trm genes. Thus, repeated antigen exposure arms circulating memory CD8T cells with enhanced capacity to form long-lived populations of Trm that enhance control of viral infections of the mLN.