期刊
JOURNAL OF IMMUNOLOGY
卷 191, 期 4, 页码 1614-1624出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1300479
关键词
-
类别
资金
- Veterans Affairs Merit Review Grant [1I01BX000600-01]
- National Institutes of Health/National Institute of Allergy and Infectious Diseases [1AI 071110, ARRA 3RO1AI71110-02S1, 1RO1 AI083705, U01 AI082966, P30 AI027767]
- American College of Rheumatology-Within-Our-Reach, the Rheumatology Research Foundation
- Alliance for Lupus Research
- Arthritis Foundation
- Lupus Research Institute
- National Institute of Allergy and Infectious Diseases, National Institutes of Health
- National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases [NIAMS] [P30 AR048311]
- University of Alabama at Birmingham Analytic Imaging and Immunoreagents Core (NIAMS) [P30 AR048311]
Germinal centers (GCs) provide a microenvironment that promotes and regulates the interactions of B cells with follicular Th (T-FH) cells. In this study, we show that there are significantly higher frequencies of CXCR5(+)ICOS(+) T-FH cells in autoimmune BXD2 mice, and these cells express both IL-21R and IL-17RA. Although IL-17 and IL-21 are both important for the formation of spontaneous GCs and development of pathogenic autoantibodies, IL-21, but not IL-17, is required for the proper development of T-FH cells in BXD2 mice. The total numbers of T-FH cells and their ability to induce B cell responses in vitro were not affected by a deficiency of IL-17RA in BXD2-Il17ra(-/-) mice, the majority of CXCR5(+) T-FH cells from BXD2-Il17ra(-/-) mice were, however, not localized in the GC light zone (LZ). Interruption of IL-17 signaling, either acutely by AdIL-17R:Fc or chronically by Il17ra(-/-), disrupted T-FH-B interactions and abrogated the generation of autoantibody-forming B cells in BXD2 mice. IL-17 upregulated the expression of regulator of G-protein signaling 16 (RGS16) to promote the ability of T-FH to form conjugates with B cells, which was abolished in T-FH cells from BXD2-Rgs16(-/-) mice. The results suggests that IL-17 is an extrinsic stop signal that it acts on postdifferentiated IL-17RA(+) T-FH to enable its interaction with responder B cells in the LZ niche. These data suggest a novel concept that T-FH differentiation and its stabilization in the LZ are two separate checkpoints and that IL-21 and IL-17 act at each checkpoint to enable pathogenic GC development.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据