Bruton's tyrosine kinase promotes persistence of mature anti-insulin B cells.
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.
Division of Rheumatology and Immunology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232;
Rachel H
RH
Bonami
Allison M
AM
Sullivan
James B
JB
Case
Hannah E
HE
Steinberg
Kristen L
KL
Hoek
Wasif N
WN
Khan
Peggy L
PL
Kendall
D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology; D007136:Immunoglobulins / Q000276:immunology; D007328:Insulin / Q000276:immunology*; D007330:Insulin Antibodies / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000276:immunology*; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism
C014609:IgK; D007136:Immunoglobulins; D007328:Insulin; D007330:Insulin Antibodies; D011947:Receptors, Antigen, B-Cell; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625951:Btk protein, mouse