The Adaptor Molecule Act1 Regulates BAFF Responsiveness and Self-Reactive B Cell Selection during Transitional B Cell Maturation

被引:17
作者
Giltiay, Natalia V. [1 ]
Lu, Yi [1 ]
Allman, David [2 ]
Jorgensen, Trine N. [1 ]
Li, Xiaoxia [1 ]
机构
[1] Cleveland Clin, Dept Immunol, Lemer Res Inst, Cleveland, OH 44915 USA
[2] Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA
基金
美国国家卫生研究院;
关键词
NECROSIS-FACTOR FAMILY; MARGINAL ZONE; SJOGRENS-SYNDROME; CUTTING EDGE; AUTOIMMUNE MANIFESTATIONS; LYMPHOCYTE DEVELOPMENT; ACTIVATING FACTOR; SURVIVAL; MICE; PATHWAYS;
D O I
10.4049/jimmunol.0903312
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
The transitional stage is a key check-point for elimination of autoreactive B cells in the periphery. This selection process requires fine regulation of signals received through BCR and B cell activating factor (BAFF) receptor. We previously identified the adaptor molecule Act1 as a negative regulator of BAFF-mediated signaling. Deficiency of Act1 in mice results in peripheral B cell hyperplasia and development of autoimmunity. In this study, we demonstrate that Act1 plays a critical role in the regulation of transitional B cell survival and maturation. We found that the ratio of late-transitional (T2) to early-transitional (T1) cells was increased in spleens from Act1-deficient mice. Moreover, BAFF stimulation induced better T1 cell survival and promoted more efficient maturation of T1 cells into T2 cells ex vivo in the absence of Act1. BAFF stimulation induced higher levels of the anti-apoptotic Bcl-2 member Mc1-l in Act1-deficient T1 cells than in wild-type control cells, suggesting that Mcl-1 might be one of the key effector molecules for BAFF-mediated survival of the Act1-deficient transitional B cells. Importantly, costimulation with BAFF was able to rescue Act1-deficient T1 cells from BCR-induced apoptosis more effectively than Act1-sufficient T1 B cells. Finally, by using hen egg lysozyme double transgenic mice, we demonstrated that Act1 deficiency can promote the maturation of Ag-specific autoreactive B cells. Taken together, our results suggest that the transitional stage is a critical point of action of Act1 in the elimination of autoreactive B cells and in the regulation of peripheral B cell homeostasis. The Journal of Immunology, 2010, 185: 99-109.
引用
收藏
页码:99 / 109
页数:11
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