Autoimmune Risk Allele of PTPN22 influences early events post viral infection

Abstract

Abstract The PTPN22 alternative allele, PTPN22 1858T, is present in 5–10% of the North American population and is considered the highest autoimmune, non-HLA, risk allele. Extensive work has been done to better understand this allele in the context of autoimmune disorders. However, the role of PTPN22 1858T in the context of viral infection remains incompletely defined. Our lab has previously defined a role for Ptpn22 in generating T cell exhaustion during chronic viral infection. Yet, the mechanism by which it is acting and how the alternative allele effects T cell exhaustion remains unknown. To directly determine this we used CRISPR/Cas9 technology to independently generate mice expressing the human-relevant Ptpn22 alternative allele. Using the well-established LCMV-cl13 infection model in our mice, we tested the hypothesis that pleiotropic effects of Ptpn22 contributes to T cell exhaustion and chronic viral infection. We address this through examination of the role of Ptpn22 in numerous immune cells contributing to viral clearance in vivo. Since early events post-infection drastically influence persistent viral infection we began our studies characterizing splenic organization, cytokines, immune cell infiltration of target organs, and viral load at 1 and 3 days post infection in our mice. Next, we further define how the Ptpn22 alternative allele effects APC functions required for proper anti-viral immune response. Lastly, we determine the state of viral clearance and T cell exhaustion at late time points post-infection in our system. Results of these studies give valuable insight into the role of Ptpn22 in multiple immune cell types that contribute to chronic viral infection and T cell exhaustion.