The Pro-autoimmune allele of tyrosine phosphatase PTPN22 enhances anti-viral and anti-tumor immunity

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 to clear pathogens and tumors, the influence of PTPN22, and its pro-autoimmune allele, have on viral and tumorigenic conditions is still being 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 wild-type mice. Consistent with these results, R619W mice have enhanced antigen-specific T cell activation during viral infection and increased tumor-infiltrating Th1 CD4 T cells. Additionally, we define an underlying mechanism by which Ptpn22 promotes PD-L1 expression on conventional dendritic cells (cDCs) in wild-type mice, but is abrogated in R619W mice during disease. Lastly, R619W expression in lymphocytes alone can enhance T cell activation; however, the combination of R619W expressing lymphocytes and DCs enhances T cell activation even more. 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.