Bruton's tyrosine kinase synergizes with Notch2 to govern marginal zone B cells in nonobese diabetic mice

James B. Case, Rachel H. Bonami, Lindsay E. Nyhoff, Hannah E. Steinberg, Allison M. Sullivan, Peggy L. Kendall

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

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 antiinsulin 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 diseaseintervention strategies.

Original languageEnglish
Pages (from-to)61-70
Number of pages10
JournalJournal of Immunology
Volume195
Issue number1
DOIs
StatePublished - Jul 1 2015

Fingerprint

Dive into the research topics of 'Bruton's tyrosine kinase synergizes with Notch2 to govern marginal zone B cells in nonobese diabetic mice'. Together they form a unique fingerprint.

Cite this