Bruton's Tyrosine Kinase Synergizes with Notch2 To Govern Marginal Zone B Cells in Nonobese Diabetic Mice.

Case JB, Bonami RH, Nyhoff LE, Steinberg HE, Sullivan AM, Kendall PL
J Immunol. 2015 195 (1): 61-70

PMID: 26034172 · PMCID: PMC4551465 · DOI:10.4049/jimmunol.1400803

Expansion of autoimmune-prone marginal zone (MZ) B cells has been implicated in type 1 diabetes. To test disease contributions of MZ B cells in NOD mice, Notch2 haploinsufficiency (Notch2(+/-)) was introduced but failed to eliminate the MZ, as it does in C57BL/6 mice. Notch2(+/-)/NOD have MZ B cell numbers similar to those of wild-type C57BL/6, yet still develop diabetes. To test whether BCR signaling supports Notch2(+/-)/NOD MZ B cells, Bruton's tyrosine kinase (Btk) deficiency was introduced. Surprisingly, MZ B cells failed to develop in Btk-deficient Notch2(+/-)/NOD mice. Expression of Notch2 and its transcriptional target, Hes5, was increased in NOD MZ B cells compared with C57BL/6 MZ B cells. Btk deficiency reduced Notch2(+/-) signaling exclusively in NOD B cells, suggesting that BCR signaling enhances Notch2 signaling in this autoimmune model. The role of BCR signaling was further investigated using an anti-insulin transgenic (Tg) BCR (125Tg). Anti-insulin B cells in 125Tg/Notch2(+/-)/NOD mice populate an enlarged MZ, suggesting that low-level BCR signaling overcomes reliance on Notch2. Tracking clonotypes of anti-insulin B cells in H chain-only VH125Tg/NOD mice showed that BTK-dependent selection into the MZ depends on strength of antigenic binding, whereas Notch2-mediated selection does not. Importantly, anti-insulin B cell numbers were reduced by Btk deficiency, but not Notch2 haploinsufficiency. These studies show that 1) Notch2 haploinsufficiency limits NOD MZ B cell expansion without preventing type 1 diabetes, 2) BTK supports the Notch2 pathway in NOD MZ B cells, and 3) autoreactive NOD B cell survival relies on BTK more than Notch2, regardless of MZ location, which may have important implications for disease-intervention strategies.

MeSH Terms (19)

Animals Autoantibodies Autoimmunity B-Lymphocyte Subsets Cell Differentiation Cell Survival Diabetes Mellitus, Experimental Female Gene Expression Regulation Immunoglobulin Heavy Chains Insulin Male Mice Mice, Inbred C57BL Mice, Inbred NOD Protein-Tyrosine Kinases Receptor, Notch2 Receptors, Antigen, B-Cell Signal Transduction

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