Bruton's Tyrosine Kinase Promotes Persistence of Mature Anti-Insulin B Cells
Bruton's Tyrosine Kinase Promotes Persistence of Mature Anti-Insulin B Cells
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DOI：
10.4049/jimmunol.1300125
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发表时间：
2014-02-15
影响因子：
4.4
通讯作者：
Kendall, Peggy L.
中科院分区：
文献类型：
--
作者：
Bonami, Rachel H.;Sullivan, Allison M.;Kendall, Peggy L.
自身反应性B淋巴细胞对于T细胞介导的1型糖尿病（T1 D）的发展至关重要。细胞质布鲁顿酪氨酸激酶（BTK）是B细胞信号传导的关键组分，并且其在T1 D易感NOD小鼠中的缺失显著降低糖尿病。然而，BTK在自身反应性B细胞的存活和功能中的作用尚不清楚。为了评估BTK的贡献，我们使用了B细胞表达抗胰岛素BCR（125 Tg）并促进T1 D的小鼠，尽管它们是无反应性的。将Btk缺陷杂交到125 Tg小鼠上揭示，与不成熟的B细胞相反，成熟的抗胰岛素B细胞精确地依赖于BTK，因为它们的数量减少了95%。BTK激酶结构域抑制在成熟的抗胰岛素B细胞中再现了这种效应，在过渡阶段影响较小。抗胰岛素B细胞对BTK的依赖性增加在Igk基因座定点模型中变得特别明显，其中50%的B细胞将其BCR编辑为非胰岛素特异性; Btk缺乏优先消耗卵泡和边缘区B细胞亚群中的胰岛素结合剂。持续存在的少数Btk缺陷型抗胰岛素B细胞仍然能够内化Ag并侵入胰岛。因此，在125 Tg/NOD小鼠中，BTK的丧失并不像在具有正常B细胞库的NOD小鼠中那样显著降低糖尿病发病率。因此，BTK靶向可能不会损害自身反应性抗胰岛素B细胞功能，但它可以通过降低成熟自身反应性B细胞的相对可用性来提供内源性库中的保护。
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 Igk 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 antiinsulin 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.