The characterization of MCMV specific Qa-1-restricted CD8+ T cells

Abstract While MHC class Ia-restricted classical CD8+ T cells have been widely shown to participate in the immune response to viral infection, little is known about the MHC class Ib-restricted non-classical CD8+ T cell response. Our laboratory recently demonstrated that during murine cytomegalovirus (MCMV), a well-established model system for human CMV, adoptively transferred non-classical CD8+ T cells are sufficient to protect Kb Db RAG1−/− mice from lethality. We sought to further characterize this protective population, which is largely Qa-1-restricted. Using Kb Db−/− and Kb Db−/−. SJL mice, we are able to track the same original population of T cells through iterative adoptive transfers in multiple hosts. Following MCMV infection of new hosts, these T cells continue to play an active role in viral protection and exhibit both effector and memory phenotypes. Strikingly, following multiple challenges, an enriched clonal CD8+ T cell response is observed. While certain strains of human CMV encode a mimic of the canonical peptide binding partner for Qa-1, MCMV does not have a similar mechanism. Rather, our data show that these T cells are stimulated by an MCMV-derived antigen that is recognized by CD8+ T cells with limited αβ TCR diversity. The population we describe may act as a compensatory immune mechanism when MHC class Ia is targeted by CMV immunoevasins. Taken together, these data demonstrate that an MCMV-derived peptide is presented by Qa-1, necessary for an MCMV-specific activation of non-classical CD8+ T cells, and may be of importance for viral protection when classical CD8+ T cell immunity is compromised. This work is supported by NIH Research Grants AI046709 and AI12221, and was supported by a T32 Training Grant in Molecular and Cell Biology and Biochemistry in years 2019-2020. Shanelle Reilly is also supported by research supplement R01 3AI046709-18S1 to promote diversity.