Deletion of Ptpn2 in B cells promotes autoimmunity via TLR and JAK/STAT signaling.

Abstract

Autoimmunity arises when self-reactive B and T cells target the body's own tissues, with B cells contributing through antigen presentation as well as production of autoantibodies and proinflammatory cytokines. Genome wide association studies (GWAS) and recent identification of loss-of-function gene variants in individuals with young-onset autoimmunity have highlighted a role for protein tyrosine phosphatase nonreceptor type 2 (PTPN2) in development of autoimmunity. While prior studies have focused on the mechanism of Ptpn2 in T cells and other cell types, its function in B cells has not been explored. To test the B cell-intrinsic roles of Ptpn2, we generated a B cell-specific deletion of Ptpn2 in mice (Mb1-Cre;Ptpn2fl/fl). We found that loss of Ptpn2 in B cells promoted organ inflammation, increased the frequency of age/autoimmune-associated B cells (ABCs) and plasmablasts in the periphery, and increased circulating autoantibodies. Moreover, we found that Ptpn2 acted as a negative regulator of the JAK/STAT and TLR7 pathways in B cells. In line with this, treatment of B cells from Mb1-Cre;Ptpn2fl/fl mice with IFN-γ and TLR7 agonist lead to enhanced differentiation into ABCs. These findings highlight the critical roles of Ptpn2 in B cell function and its potential as a key regulator in preventing B cell associated autoimmunity.