Abstract
Our understanding of memory CD8(+) T cells has been largely derived from acute, systemic infection models. However, memory CD8(+) T cells generated from mucosal infection exhibit unique properties and, following respiratory infection, are not maintained in the lung long term. To better understand how infection route modifies memory differentiation, we compared murine CD8(+) T cell responses to a vesicular stomatitis virus (VSV) challenge generated intranasally (i.n.) or i.v. The i.n. infection resulted in greater peak expansion of VSV-specific CD8(+) T cells. However, this numerical advantage was rapidly lost during the contraction phase of the immune response, resulting in memory CD8(+) T cell numerical deficiencies when compared with i.v. infection. Interestingly, the antiviral CD8(+) T cells generated in response to i.n. VSV exhibited a biased and sustained proportion of early effector cells (CD127(lo)KLRG1(lo)) akin to the developmental program favored after i.n. influenza infection, suggesting that respiratory infection broadly favors an incomplete memory differentiation program. Correspondingly, i.n. VSV infection resulted in lower CD122 expression and eomesodermin levels by VSV-specific CD8(+) T cells, further indicative of an inferior transition to bona fide memory. These results may be due to distinct (CD103(+)CD11b(+)) dendritic cell subsets in the i.n. versus i.v. T cell priming environments, which express molecules that regulate T cell signaling and the balance between tolerance and immunity. Therefore, we propose that distinct immunization routes modulate both the quality and quantity of antiviral effector and memory CD8(+) T cells in response to an identical pathogen and should be considered in CD8(+) T cell-based vaccine design.