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

Bonami RH, Sullivan AM, Case JB, Steinberg HE, Hoek KL, Khan WN, Kendall PL
J Immunol. 2014 192 (4): 1459-70

PMID: 24453243 · PMCID: PMC4083749 · DOI:10.4049/jimmunol.1300125

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 Ig╬║ 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.

MeSH Terms (14)

Agammaglobulinaemia Tyrosine Kinase Animals B-Lymphocytes Cells, Cultured Diabetes Mellitus, Type 1 Immunoglobulins Insulin Insulin Antibodies Mice Mice, Inbred C57BL Mice, Inbred NOD Mice, Transgenic Protein-Tyrosine Kinases Receptors, Antigen, B-Cell

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