Viral and tumor immunity is enhanced in mice expressing the pro-autoimmune allele of tyrosine phosphatase Ptpn22

Abstract

Abstract The 1858C>T allele of the tyrosine phosphatase PTPN22 (causing amino acid substitution R620W) is present in 5–10% of the North American population and is strongly associated with numerous autoimmune diseases. Specifically, this alternative allele affects lymphocyte activation, toll-like receptor signaling, and cytokine production in various autoimmune contexts. Despite the importance of these inflammatory networks in pathogen and tumor clearance, the influence of PTPN22 and its pro-autoimmune allele have on viral and tumorigenic conditions is poorly defined. To interrogate these roles, we used CRISPR/Cas9 to generate mice expressing the Ptpn22 R619W molecule, which is the ortholog of R620W in humans. Using LCMV-cl13 infection and B16 tumor models, we tested the hypothesis that pleiotropic effects of Ptpn22 R619W enhances anti-viral and anti-tumor immunity. Importantly, R619W bearing mice have less tumor burden and clear chronic viral infection faster than wildtype mice. Consistent with these results, R619W mice have enhanced antigen-specific T cell activation during viral infection and more tumor infiltrating activated T cells. Also, R619W bearing mice have a more immunostimulatory cDC phenotype during disease. As this gene is expressed in all immune cells, we interrogated the role that the R619W molecule has on T cell intrinsic versus extrinsic mechanisms of T cell activation. We show an additive mechanism in which both T cell and non-T cell compartments expressing the R619W molecule cause the most T cell activation. Our results suggest that a pro-autoimmune allele can be beneficial by promoting anti-viral and anti-tumor immune responses through multiple immune cell types, and may have a protective effect in these diseases.