Bruton's tyrosine kinase promotes persistence of mature anti-insulin B cells

Rachel H. Bonami, Allison M. Sullivan, James B. Case, Hannah E. Steinberg, Kristen L. Hoek, Wasif Khan, Peggy L. Kendall

Research output: Contribution to journalArticle

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Abstract

Autoreactive B lymphocytes are essential for the development of T cell-mediated type 1 diabetes (T1D). Cytoplasmic Bruton's tyrosine kinase (BTK) is a key component of B cell signaling, and its deletion in T1D-prone NOD mice significantly reduces diabetes. However, the role of BTK in the survival and function of autoreactive B cells is not clear. To evaluate the contributions of BTK, we used mice in which B cells express an anti-insulin BCR (125Tg) and promote T1D, despite being anergic. Crossing Btk deficiency onto 125Tg mice reveals that, in contrast to immature B cells, mature anti-insulin B cells are exquisitely dependent upon BTK, because their numbers are reduced by 95%. BTK kinase domain inhibition reproduces this effect in mature anti-insulin B cells, with less impact at transitional stages. The increased dependence of anti-insulin B cells on BTK became particularly evident in an Igκ locus site-directed model, in which 50% of B cells edit their BCRs to noninsulin specificities; Btk deficiency preferentially depletes insulin binders from the follicular and marginal zone B cell subsets. The persistent few Btk-deficient anti-insulin B cells remain competent to internalize Ag and invade pancreatic islets. As such, loss of BTK does not significantly reduce diabetes incidence in 125Tg/NOD mice as it does in NOD mice with a normal B cell repertoire. Thus, BTK targeting may not impair autoreactive anti-insulin B cell function, yet it may provide protection in an endogenous repertoire by decreasing the relative availability of mature autoreactive B cells.

Original languageEnglish
Pages (from-to)1459-1470
Number of pages12
JournalJournal of Immunology
Volume192
Issue number4
DOIs
StatePublished - Feb 15 2014

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B-Lymphocytes
Insulin
Inbred NOD Mouse
Type 1 Diabetes Mellitus
Agammaglobulinaemia tyrosine kinase
B-Lymphocyte Subsets
B-Lymphoid Precursor Cells
Islets of Langerhans
Phosphotransferases
T-Lymphocytes
Incidence

ASJC Scopus subject areas

  • Immunology

Cite this

Bonami, R. H., Sullivan, A. M., Case, J. B., Steinberg, H. E., Hoek, K. L., Khan, W., & Kendall, P. L. (2014). Bruton's tyrosine kinase promotes persistence of mature anti-insulin B cells. Journal of Immunology, 192(4), 1459-1470. https://doi.org/10.4049/jimmunol.1300125

Bruton's tyrosine kinase promotes persistence of mature anti-insulin B cells. / Bonami, Rachel H.; Sullivan, Allison M.; Case, James B.; Steinberg, Hannah E.; Hoek, Kristen L.; Khan, Wasif; Kendall, Peggy L.

In: Journal of Immunology, Vol. 192, No. 4, 15.02.2014, p. 1459-1470.

Research output: Contribution to journalArticle

Bonami, RH, Sullivan, AM, Case, JB, Steinberg, HE, Hoek, KL, Khan, W & Kendall, PL 2014, 'Bruton's tyrosine kinase promotes persistence of mature anti-insulin B cells', Journal of Immunology, vol. 192, no. 4, pp. 1459-1470. https://doi.org/10.4049/jimmunol.1300125
Bonami, Rachel H. ; Sullivan, Allison M. ; Case, James B. ; Steinberg, Hannah E. ; Hoek, Kristen L. ; Khan, Wasif ; Kendall, Peggy L. / Bruton's tyrosine kinase promotes persistence of mature anti-insulin B cells. In: Journal of Immunology. 2014 ; Vol. 192, No. 4. pp. 1459-1470.
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