PTPN22-CD45 dual phosphatase retrograde feedback enhances TCR signaling and autoimmunity

Protein tyrosine phosphatase nonreceptor type 22 (PTPN22) is encoded by a gene strongly associated with lupus and other autoimmune diseases. PTPN22 regulates T cell receptor (TCR) signaling through dephosphorylation of the kinases lymphocyte-specific protein tyrosine kinase (LCK) and zeta-chain-associated protein kinase 70 (ZAP70). The regulation of PTPN22 remains poorly understood. Here, we identify PTPN22 Ser⁴⁴⁹ as a protein kinase A phosphorylation site, which is triggered by TCR engagement and is hyperphosphorylated in lupus peripheral blood cells. PTPN22 Ser⁴⁴⁹ phosphorylation selectively lowered the affinity of PTPN22 for ZAP70 versus LCK but also indirectly suppressed inhibitory LCK Tyr¹⁹² phosphorylation through a ZAP70-CD45 signaling axis. The resulting dephosphorylation of LCK Tyr¹⁹² not only enhanced TCR signaling but also modulated pathway activation downstream the TCR. In vivo loss of PTPN22 Ser⁴⁴⁹ phosphorylation reduced T cell responses and suppressed experimental lupus nephritis. These results suggest that PTPN22 Ser⁴⁴⁹ phosphorylation promotes a CD45-mediated retrograde ZAP70-LCK feedback loop that enhances T cell responses and promotes autoimmunity.