The Role of an Autoimmune Disease-Associated Phosphatase in Dendritic Cell Biology

PTPN22 encodes the human lymphoid tyrosine phosphatase, Lyp, a protein exclusively expressed in hematopoietic cells and involved in numerous signaling pathways. Lyp has been of great interest since the discovery of a variant affiliated with multiple autoimmune diseases. The variant, PTPN22-C1858T, has been investigated in human and animal models with conflicting results. Some groups claim the variant causes a gain-of-function effect while others claim a loss- of-function effect. This study sheds light on how the variant influences the dendritic cell (DC) network, a network comprised of multiple subpopulations, each with specific and overlapping functions. Here we show mice expressing the orthologous variant have abnormal splenic DC frequencies and distribution, with an increase in the CD4+ conventional type 2 DC population. Furthermore, all DC subpopulations investigated consistently displayed increased expression of CD40, indicating a hyperactive phenotype. Additionally, bone marrow-derived DCs produced more IL-12 after TLR9 stimulation and collectively these factors may contribute to autoimmune disease.M.Sc