Regulation of B cell homeostasis by Ptpn22 contributes to type 1 diabetes in NOD mice

Purpose A coding variant in PTPN22 (C1858T) is one of the most important genetic risk factors in type 1 diabetes (T1D). The role of the PTPN22 risk allele in B cells is still incompletely understood and has not been investigated directly in T1D. This study aimed to explore the role of PTPN22 in the homeostasis of B cells and its influence in T1D. Methods Wild-type (WT) and Ptpn22 inducible knockdown (KD) NOD mice were treated with 200 μg/ml doxycycline at the age of 10 weeks for 1–2 months. B cell compositions in the bone marrow, peritoneal cavity and spleen were examined. The pathogenicity of Ptpn22 KD B cells was explored by adoptive cell transfer. Results Ptpn22 silencing increased the frequency of recirculating mature B cells in the bone marrow, decreased the frequency of B-1a cells in the peritoneal cavity and suppressed the formation of marginal zone B cells and plasma cells in the spleen. Changes in the composition of the peripheral B cell compartment caused by altered cell proliferation while rates of apoptosis were not affected. Significantly, co-transfer of Ptpn22 KD B cells with NY8.3 diabetogenic T cells diminished the frequency of diabetes in recipient NOD. scid mice compared with co-transfer of WT B cells. Conclusions Our study constitutes the first functional study of Ptpn22 in B cells in NOD mice. Our findings suggest that Ptpn22 variation contributes to T1D by modifying the B cell compartment and support a gain-of-function for the PTPN22 disease variant.