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

Protective lung tissue-resident memory CD8.sup.+T cells (Trm) form after influenza A virus (IAV) infection. We show that IAV infection of mice generates CD69.sup.+CD103.sup.+and other memory CD8.sup.+T cell populations in lung-draining mediastinal lymph nodes (mLNs) from circulating naive or memory CD8.sup.+T cells. Repeated antigen exposure, mimicking seasonal IAV infections, generates quaternary memory (4M) CD8.sup.+T cells that protect mLN from viral infection better than 1M CD8.sup.+T cells. Better protection by 4M CD8.sup.+T cells associates with enhanced granzyme A/B expression and stable maintenance of mLN CD69.sup.+CD103.sup.+4M CD8.sup.+T cells, vs the steady decline of CD69.sup.+CD103.sup.+1M CD8.sup.+T cells, paralleling the durability of protective CD69.sup.+CD103.sup.+4M 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 CD8.sup.+T cells with enhanced capacity to form long-lived populations of Trm that enhance control of viral infections of the mLN.