Garvan Institute of Medical Research, Darlinghurst, Sydney NSW 2010, Australia.
J Exp Med. 2010 Dec 20;207(13):2895-906. doi: 10.1084/jem.20100064. Epub 2010 Nov 22.
Maturation and selection of high-affinity B cell clones in the germinal center (GC) relies on support from T follicular helper (T(FH)) cells. T(FH) cells are characterized by their localization to the B cell follicle and their high expression of the costimulatory molecules ICOS and PD1 and the cytokine IL-21, which promotes immunoglobulin (Ig) class switching and production by B cells. We show that the heterodimeric cytokine IL-27 is critical for the function of T(FH) cells and for normal and pathogenic GC responses. IL-27 signaling to T cells results in the production of IL-21, a known autocrine factor for the maintenance of T(FH) cells, in a STAT3-dependent manner. IL-27 also enhances the survival of activated CD4(+) T cells and the expression of T(FH) cell phenotypic markers. In vivo, expression of the IL-27Rα chain is required to support IL-21 production and T(FH) cell survival in a T cell-intrinsic manner. The production of high-affinity antibodies is reduced, and pristane-elicited autoantibodies and glomerulonephritis are significantly diminished, in Il27ra(-/-) mice. Together, our data show a nonredundant role for IL-27 in the development of T cell-dependent antibody responses.
生发中心（GC）中高亲和力 B 细胞克隆的成熟和选择依赖于滤泡辅助性 T（T(FH)）细胞的支持。T(FH)细胞的特征是定位于 B 细胞滤泡，高表达共刺激分子 ICOS 和 PD1 以及细胞因子 IL-21，后者促进 B 细胞的免疫球蛋白（Ig）类别转换和产生。我们表明，细胞因子 IL-27 二聚体对于 T(FH)细胞的功能以及正常和病理性 GC 反应至关重要。IL-27 信号传导至 T 细胞会导致 IL-21 的产生，IL-21 是维持 T(FH)细胞的已知自分泌因子，这是一种依赖 STAT3 的方式。IL-27 还增强了活化的 CD4(+) T 细胞的存活和 T(FH)细胞表型标记的表达。在体内，以 T 细胞内在的方式，IL-27Rα 链的表达对于支持 IL-21 的产生和 T(FH)细胞的存活是必需的。在 Il27ra(-/-) 小鼠中，高亲和力抗体的产生减少，并且天然烷化剂诱发的自身抗体和肾小球肾炎显著减少。总之，我们的数据表明 IL-27 在 T 细胞依赖性抗体反应的发展中具有非冗余作用。
