Abstract
Establishing functional tissue-resident memory (TRM) cells at sites of infection is a newfound objective of T cell vaccine design. To directly assess the impact of antigen stimulation strength on memory CD8 T cell formation and function during a persistent viral infection, we created a library of mouse polyomavirus (MuPyV) variants with substitutions in a subdominant CD8 T cell epitope that exhibit a broad range of efficiency in stimulating TCR transgenic CD8 T cells. By altering a subdominant epitope in a nonstructural viral protein and monitoring memory differentiation of donor monoclonal CD8 T cells in immunocompetent mice, we circumvented potentially confounding changes in viral infection levels, virus-associated inflammation, size of the immunodominant virus-specific CD8 T cell response, and shifts in TCR affinity that may accompany temporal recruitment of endogenous polyclonal cells. Using this strategy, we found that antigen stimulation strength was inversely associated with the function of memory CD8 T cells during a persistent viral infection. We further show that CD8 TRM cells recruited to the brain following systemic infection with viruses expressing epitopes with suboptimal stimulation strength respond more efficiently to challenge CNS infection with virus expressing cognate antigen. These data demonstrate that the strength of antigenic stimulation during recruitment of CD8 T cells influences the functional integrity of TRM cells in a persistent viral infection.
Highlights
Following TCR engagement, pathogen-specific naïve CD8 T cells rapidly expand to generate a large effector population to counter primary infection, with a small population of memory CD8 T cells concomitantly generated to provide accelerated immunity to re-infection
The DbLT359 and DbLT638 mouse polyomavirus (MuPyV) epitopes share homology with SV40 Large T antigen (LT) epitopes in B6 mice; e.g., mutagenizing 4 of 10 codons in LT359 to match its homologous sequence in SV40 LT yielded an MuPyV mutant virus expressing a dominant epitope recognized by monoclonal SV40 LT-specific CD8 T cells [26]
The subdominant MuPyV LT amino acids 638–646 (LT638) epitope and the “immunorecessive” SV40 LT epitope corresponding to amino acids 489–497, designated TagV, differ by three residues in the amino-half of their epitopes (Table 1)
Summary
Following TCR engagement, pathogen-specific naïve CD8 T cells rapidly expand to generate a large effector population to counter primary infection, with a small population of memory CD8 T cells concomitantly generated to provide accelerated immunity to re-infection. The canonical naïve-to-effector/memory differentiation profile for CD8 T cell responses to microbial infections is derived from analyzing T cell responses in secondary lymphoid organs. Tissue-resident memory (TRM) cells apparently circumvent this differentiation schema by “locking” themselves in an effector-poised state having a transcription profile distinct from circulating central-memory and effector-memory T cells [6,7,8,9,10]. Most studies to date have characterized TRM cells in mucosal tissue barriers (e.g., skin, lung, gut, and female reproductive tract), where they act to provide rapid protection against secondary infections [11,12,13,14,15,16]. Several viral CNS infection mouse models have described the establishment of TRM cells in the brain. Using intracerebral (i.c.) inoculation with lymphocytic choriomeningitis virus (LCMV), Steinbach et al showed that virus-specific CD8 brainTRM cells, in the absence of circulating antiviral CD8 T cells, conferred protection to CNS challenge with LCMV [12]
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