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TYK2 is a JAK family member that functions downstream of multiple cytokine receptors. Genome wide association studies have linked a SNP (rs34536443) within  TYK2  encoding a Proline to Alanine substitution at amino acid 1104, to protection from multiple autoimmune diseases including systemic lupus erythematosus (SLE) and multiple sclerosis (MS). The protective role of this SNP in autoimmune pathogenesis, however, remains incompletely understood. Here we found that T follicular helper (Tfh) cells, switched memory B cells, and IFNAR signaling were decreased in healthy individuals that expressed the protective variant  TYK2   A 1104  ( TYK2   P  ). To study this variant  in vivo , we developed a knock-in murine model of this allele. Murine  Tyk2   P   expressing T cells homozygous for the protective allele, but not cells heterozygous for this change, manifest decreased IL-12 receptor signaling, important for Tfh lineage commitment. Further, homozygous  Tyk2   P   T cells exhibited diminished  in vitro  Th1 skewing. Surprisingly, despite these signaling changes,  in vivo  formation of Tfh and GC B cells was unaffected in two models of T cell dependent immune responses and in two alternative SLE models. TYK2 is also activated downstream of IL-23 receptor engagement. Here, we found that  Tyk2   P   expressing T cells had reduced IL-23 dependent signaling as well as a diminished ability to skew toward Th17  in vitro . Consistent with these findings, homozygous, but not heterozygous,  Tyk2   P   mice were fully protected in a murine model of MS. Homozygous  Tyk2   P   mice had fewer infiltrating CD4 +  T cells within the CNS. Most strikingly, homozygous mice had a decreased proportion of IL-17 + /IFNγ + , double positive, pathogenic CD4 +  T cells in both the draining lymph nodes (LN) and CNS. Thus, in an autoimmune model, such as EAE, impacted by both altered Th1 and Th17 signaling, the  Tyk2   P   allele can effectively shield animals from disease. Taken together, our findings suggest that TYK2 P  diminishes IL-12, IL-23, and IFN I signaling and that its protective effect is most likely manifest in the setting of autoimmune triggers that concurrently dysregulate at least two of these important signaling cascades.

The TYK2-P1104A Autoimmune Protective Variant Limits Coordinate Signals Required to Generate Specialized T Cell Subsets