Diverse CD8 T cell responses to infection revealed by the collaborative cross

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Abstract Enhanced host protection against re-infection requires generation of memory T cells of sufficient quantity and functional quality. Unlike well-studied inbred mice, T cell responses of diverse size and quality are generated following infection of humans and outbred mice. Thus, additional models are needed that more accurately reflect variation in immune outcomes in genetically diverse populations and to uncover underlying genetic causes. The Collaborative Cross (CC), a large recombinant inbred panel of mice, is an ideal model in this pursuit due to the high degree of genetic variation present and because it allows for assessment of genetic factors underlying unique phenotypes. The objectives of this study were to determine if the CC models diversity of immune outcomes seen in the human population, and if it could be used to identify genetic factors contributing to the generation of qualitatively and quantitatively distinct memory CD8 T cells. To this end, we analyzed the T cell response following acute LCMV Armstrong infection in 47 strains of CC mice. We found variability in resting immune cell composition and adaptive immune responses generated among CC strains in response to infection and reveal quantitative trait loci and candidate genes responsible for generation of CD62L+ memory CD8 T cells. Our results support the use of the CC to model diversity in immune responses observed in genetically diverse organisms and to uncover regulatory networks and host genetic factors underlying diverse immune outcomes following infection. This study and future studies utilizing the CC have the potential to improve translational efforts for the generation of protective immune responses against cancer and infections of global importance.

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