PTPN22 is overexpressed and has a dual role in regulating B cell receptor signaling in B1 B cells

The phosphatase PTPN22 is markedly overexpressed in chronic lymphocytic leukemia (CLL) B cells and has been implicated in the pathogenesis of multiple autoimmune diseases. PTPN22 functions as a negative regulator of antigen-receptor signaling in T cells, but its function in B cells has remained obscure. We now show that PTPN22 is selectively overexpressed in B1 B cells and to a lesser extent in marginal zone (MZ) B cells. PTPN22 deficiency results in an increase in the percentage of B1 B cells and a reduction in the percentage of MZ B cells, which is accompanied by parallel changes in the serum levels of antibodies typically produced by these two B cell subsets. We also show that PTPN22 deficiency accelerates leukemia development in the Eμ-TCL1 mouse model of CLL and deregulates BCR signaling in the leukemic B1 B cells. Collectively, these data suggest that PTPN22 has a unique role in regulating BCR signaling and function of B1 B cells.