Dendritic cell intrinsic role of Ptpn22and its pro-autoimmune allele enhance anti-viral immunity

Abstract

Abstract The tyrosine phosphatase PTPN22 encodes the enzyme Lyp (PEP in mice) in all immune cells. 5–10% of the North American population expresses the PTPN22 autoimmunity risk allele 1858C>T (rs2476601) causing amino acid substitution R620W (R619W in mice). This mutation alters lymphocyte activation, toll-like receptor signaling, and cytokine production. Ptpn22 knockout (PEP-null) and alternative allele-expressing (PEP-R619W) mice clear persistent virus LCMV-cl13, have enhanced anti-viral T cell function, and a more immunostimulatory dendritic cell (DC) phenotype compared to wildtype (PEP-WT). Adoptive transfer studies suggest a T cell extrinsic mechanism driving enhanced T cell function in PEP-null and -R619W animals. However, the relative contribution of PEP-differing non-T cells during virus infection is not known. We hypothesize that the DC, as the sole PEP-differing cell, is the critical non-T cell driving increased T cell function and enhanced anti-viral immunity.To interrogate this, we employ CD11c Ptpn22 conditional knock out (cKO) mice and bone marrow derived DC (BMDC) cultures from PEP-WT, -null, and -R619W mice. During LCMV-cl13 infection, CD11c Ptpn22 cKO mice have improved disease outcome compared to WT mice. In a T cell: DC co-culture assay, both PEP-null and PEP-R619W DCs lead to more CD4 T cell function over WT DCs. Also, PEP-null and PEP-R619W BMDCs have changed response to virus infection. Taken together, these data suggest Ptpn22 and its allele have DC intrinsic mechanisms that alter anti-viral immunity. Results of this study lead to a more complete understanding of the cellular and molecular mechanisms, particularly in the DC, this common allele alters the immune response during infection. Supported by grants from the University of Kansas (KU), KU CBID CoBRE Research Award, and KU Center for Genomics.