Btk Supports Autoreactive B Cell Development and Protects against Apoptosis but Is Expendable for Antigen Presentation

Bruton's tyrosine kinase (Btk) propagates B cell signaling, and BTK inhibitors are in clinical trials for autoimmune disease. Although autoreactive B cells fail to develop in the absence of Btk, its role in mature cells is unknown. To address this issue, a model of conditional removal (Btkflox/Cre-ERT2) was used to excise Btk from mature transgenic B cells that recognize the pathophysiologic autoantigen insulin. Anti-insulin B cells escape central tolerance and promote autoimmune diabetes, mimicking human autoreactive cells. Lifelong Btk deficiency was previously shown to eliminate 95% of anti-insulin B cells, but in this model, mature anti-insulin B cells survived for weeks after targeted Btk deletion, even when competing with a polyclonal repertoire. BCR-stimulated cells could still signal via Syk, PLCy2, and CD22, but failed to upregulate the antiapoptotic protein Bcl-xL, and proliferation was impaired. Surprisingly, Btk-depleted anti-insulin B cells could still present Ag and activate T cells, a critical function in promoting T autoreactive cells, and preventing emergence of new ones. The Journal of Immunology, 2021, 207: 2922-2932.

Automated summary

Bruton's tyrosine kinase (Btk) plays a crucial role in inhibiting the development of mature anti-insulin B cells, removal of Btk affects the functions of anti-insulin B cells in terms of protein expression, proliferation, etc.