Host genetics play a critical role in controlling CD8 T cell function and lethal immunopathology during chronic viral infection

Effective CD8 T cell responses are vital for the control of chronic viral infections. Many factors of the host immune response contribute to the maintenance of effector CD8 T cell responses versus CD8 T cell exhaustion during chronic infection. Specific MHC alleles and the degree of MHC heterogeneity are associated with enhanced CD8 T cell function and viral control during human chronic infection. However, it is currently unclear to what extent host genetics influences the establishment of chronic viral infection. In order to examine the impact of MHC heterogeneity versus non-MHC host genetics on the development of chronic viral infection, an F1 cross of B10.D2 x B6 (D2B6F1) and BALB.B x BALB/c (BCF1) mice were infected with the clone-13 (Cl-13) strain of lymphocytic choriomeningitis virus (LCMV). Following chronic Cl-13 infection both H-2bxd D2B6F1 and BCF1 mice demonstrated increased viral control compared to homozygous mice. Strikingly, H-2bxd D2B6F1 mice on a C57BL genetic background exhibited mortality following Cl-13 infection. CD8 T cell depletion prevented mortality in Cl-13-infected D2B6F1 mice indicating that mortality was CD8 T-cell-dependent. D2B6F1 mice maintained more CD8 T cell effector cytokine production and exhibited reduced expression of the T cell exhaustion marker PD-1. In addition, D2B6F1 mice also induced a larger Th1 response than BCF1 mice and Cl-13-induced mortality in D2B6F1 mice was also dependent on CD4 T-cell-mediated IFN-γ production. Thus, following a chronic viral infection, increased functionality of the CD8 T cell response allowed for more rapid viral clearance at the cost of enhanced immunopathology dependent on both MHC diversity and the genetic background of the host.Author summary: Chronic viral infections pose a serious healthcare concern resulting in substantial mortality worldwide. Chronic viral infections result from the inability of the immune system to eliminate the virus from the infected individual. The immune system’s inability to eradicate the invading pathogen is partially due to excessive regulation of the T cell response. However, host genetics have been associated with enhanced T cell function and viral control during chronic infection. Therefore, we sought to investigate the role of host genetic diversity on the T cell response during chronic viral infection in a murine model. We found that increasing MHC heterogeneity resulted in an increased T cell response and enhanced viral control. In addition, host genetic background differences allowed for induction of a distinct CD4 T cell subset, which was associated with reduced suppression of the CD8 T cell response and enhanced viral control. Thus, specific features of the host genetic background contribute to the size and quality of the T cell response and resulting viral control. This study identifies components of the T cell response that may provide a therapeutic target to enhance T-cell-mediated viral control during chronic infection.