Competition for antigen selects T cell responses that undergo memory inflation and maintains clonal dominance during MCMV infection (P6091)

Abstract

Abstract Cytomegalovirus (CMV) establishes a life-long, persistent/latent infection. Continuous immune surveillance by CMV-specific CD8+ T cells results in their accumulation over time, a process called “memory inflation”. These “inflationary” T cells migrate systemically and comprise the largest T cell populations in humans, making CMV-based vaccines attractive. Using recombinant murine (M)CMV expressing the SIINFEKL peptide, we found that SIINFEKL-specific T cells inflated at the expense of T cells specific for other MCMV-derived peptides. However, co-infecting mice with viruses expressing and lacking SIINFEKL enabled T cells with multiple specificities to inflate, implying T cell competition for antigen at the level of the infected target. Such competition was also observed among SIINFEKL-specific T cells. Adoptively transferred OT-I T cells, which have a high affinity for the SIINFEKL peptide, were preferentially enriched shortly after infection and inhibited the inflation of host-derived T cells specific for SIINFEKL. Importantly, we observed sporadic, late rejection of OT-Is as a result of minor histocompatibility differences, and only such rejection enabled host-derived T cells to inflate robustly. These data imply that relative clonal abundance is actively maintained by competition. Together, these data show that T cell competition for antigen during MCMV infection dictates which T cell responses inflate and even which clones dominate within a response.