Journal
JOURNAL OF IMMUNOLOGY
Volume 197, Issue 1, Pages 58-67Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1600208
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- Dutch Arthritis Foundation (Reumafonds) [09-1-302, 13-2-301]
- ReumaFonds [13-2-301] Funding Source: researchfish
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Upon BCR stimulation, naive B cells increase protein levels of the key downstream signaling molecule Bruton's tyrosine kinase (BTK). Transgenic CD19-hBtk mice with B cell specific BTK overexpression show spontaneous germinal center formation, antinuclear autoantibodies, and systemic autoimmunity resembling lupus and Sjogren syndrome. However, it remains unknown how T cells are engaged in this pathology. In this study, we found that CD19-hBtk B cells were high in IL-6 and IL-10 and disrupted T cell homeostasis in vivo. CD19-hBtk B cells promoted IFN-gamma production by T cells and expression of the immune-checkpoint protein ICOS on T cells and induced follicular Th cell differentiation. Crosses with CD40L-deficient mice revealed that increased IL-6 production and autoimmune pathology in CD19-hBtk mice was dependent on B T cell interaction, whereas IL-10 production and IgM autoantibody formation were CD40L independent. Surprisingly, in Btk-overexpressing mice, naive B cells manifested increased CD86 expression, which was dependent on CD40L, suggesting that T cells interact with B cells in a very early stage of immune pathology. These findings indicate that increased BTK-mediated signaling in B cells involves a positive-feedback loop that establishes T cell propagated autoimmune pathology, making BTK an attractive therapeutic target in autoimmune disease.
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