Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
J Immunol. 2013 Aug 15;191(4):1614-24. doi: 10.4049/jimmunol.1300479. Epub 2013 Jul 15.
Germinal centers (GCs) provide a microenvironment that promotes and regulates the interactions of B cells with follicular Th (TFH) cells. In this study, we show that there are significantly higher frequencies of CXCR5(+)ICOS(+) TFH 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 TFH cells in BXD2 mice. The total numbers of TFH 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(+) TFH 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 TFH-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 TFH to form conjugates with B cells, which was abolished in TFH cells from BXD2-Rgs16(-/-) mice. The results suggests that IL-17 is an extrinsic stop signal that it acts on postdifferentiated IL-17RA(+) TFH to enable its interaction with responder B cells in the LZ niche. These data suggest a novel concept that TFH 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.
生发中心（GCs）提供了一个微环境，促进和调节 B 细胞与滤泡辅助性 T（TFH）细胞的相互作用。在这项研究中，我们表明自身免疫性 BXD2 小鼠中 CXCR5(+)ICOS(+) TFH 细胞的频率明显更高，这些细胞表达 IL-21R 和 IL-17RA。虽然 IL-17 和 IL-21 对于自发 GC 的形成和致病性自身抗体的产生都很重要，但 IL-21 而不是 IL-17，对于 BXD2 小鼠中 TFH 细胞的正常发育是必需的。在 BXD2-Il17ra(-/-) 小鼠中，IL-17RA 的缺乏并不影响 TFH 细胞的总数及其在体外诱导 B 细胞反应的能力，然而，大多数来自 BXD2-Il17ra(-/-) 小鼠的 CXCR5(+) TFH 细胞并未定位于 GC 亮区（LZ）。急性通过 AdIL-17R:Fc 或慢性通过 Il17ra(-/-) 中断 IL-17 信号，破坏了 TFH-B 相互作用，并消除了 BXD2 小鼠中自身抗体形成 B 细胞的产生。IL-17 上调 G 蛋白信号调节因子 16（RGS16）的表达，以促进 TFH 与 B 细胞形成共轭的能力，而在 BXD2-Rgs16(-/-) 小鼠的 TFH 细胞中，这种能力被消除。这些结果表明，IL-17 是一种外在的停止信号，它作用于分化后的 IL-17RA(+) TFH，使其能够在 LZ 龛位与反应性 B 细胞相互作用。这些数据表明了一个新的概念，即 TFH 分化及其在 LZ 中的稳定是两个独立的检查点，IL-21 和 IL-17 在每个检查点发挥作用，以促进致病性 GC 的发展。
