The route of priming influences the ability of respiratory virus–specific memory CD8(+) T cells to be activated by residual antigen

After respiratory virus infections, memory CD8(+) T cells are maintained in the lung airways by a process of continual recruitment. Previous studies have suggested that this process is controlled, at least in the initial weeks after virus clearance, by residual antigen in the lung-draining mediastinal lymph nodes (MLNs). We used mouse models of influenza and parainfluenza virus infection to show that intranasally (i.n.) primed memory CD8(+) T cells possess a unique ability to be reactivated by residual antigen in the MLN compared with intraperitoneally (i.p.) primed CD8(+) T cells, resulting in the preferential recruitment of i.n.-primed memory CD8(+) T cells to the lung airways. Furthermore, we demonstrate that the inability of i.p.-primed memory CD8(+) T cells to access residual antigen can be corrected by a subsequent i.n. virus infection. Thus, two independent factors, initial CD8(+) T cell priming in the MLN and prolonged presentation of residual antigen in the MLN, are required to maintain large numbers of antigen-specific memory CD8(+) T cells in the lung airways.