Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, School of Medicine, La Jolla, CA 92037, USA.
J Immunol. 2010 Jul 1;185(1):190-202. doi: 10.4049/jimmunol.0903505. Epub 2010 Jun 4.
CD4 T cell help is critical for the generation and maintenance of germinal centers (GCs), and T follicular helper (T(FH)) cells are the CD4 T cell subset required for this process. Signaling lymphocytic activation molecule (SLAM)-associated protein (SAP [SH2D1A]) expression in CD4 T cells is essential for GC development. However, SAP-deficient mice have only a moderate defect in T(FH) differentiation, as defined by common T(FH) surface markers. CXCR5(+) T(FH) cells are found within the GC, as well as along the boundary regions of T/B cell zones. In this study, we show that GC-associated T follicular helper (GC T(FH)) cells can be identified by their coexpression of CXCR5 and the GL7 epitope, allowing for phenotypic and functional analysis of T(FH) and GC T(FH) populations. GC T(FH) cells are a functionally discrete subset of further polarized T(FH) cells, with enhanced B cell help capacity and a specialized ability to produce IL-4 in a T(H)2-independent manner. Strikingly, SAP-deficient mice have an absence of the GC T(FH) cell subset and SAP(-) T(FH) cells are defective in IL-4 and IL-21 production. We further demonstrate that SLAM (Slamf1, CD150), a surface receptor that uses SAP signaling, is specifically required for IL-4 production by GC T(FH) cells. GC T(FH) cells require IL-4 and -21 production for optimal help to B cells. These data illustrate complexities of SAP-dependent SLAM family receptor signaling, revealing a prominent role for SLAM receptor ligation in IL-4 production by GC CD4 T cells but not in T(FH) cell and GC T(FH) cell differentiation.
CD4 T 细胞的辅助对于生发中心(GC)的产生和维持至关重要,而滤泡辅助性 T(T(FH))细胞是这一过程所必需的 CD4 T 细胞亚群。CD4 T 细胞中信号淋巴细胞激活分子(SLAM)相关蛋白(SAP[SH2D1A])的表达对于 GC 的发育是必不可少的。然而,SAP 缺陷型小鼠在 T(FH)分化方面仅有中度缺陷,这是通过常见的 T(FH)表面标志物定义的。CXCR5(+)T(FH)细胞存在于 GC 内,以及 T/B 细胞区的边界区域。在这项研究中,我们表明,GC 相关的滤泡辅助性 T(GC T(FH))细胞可以通过其共表达 CXCR5 和 GL7 表位来识别,从而可以对 T(FH)和 GC T(FH)群体进行表型和功能分析。GC T(FH)细胞是进一步极化的 T(FH)细胞的一个功能离散亚群,具有增强的 B 细胞辅助能力和以 T(H)2 非依赖性方式特异性产生 IL-4 的能力。引人注目的是,SAP 缺陷型小鼠缺乏 GC T(FH)细胞亚群,而 SAP(-)T(FH)细胞在产生 IL-4 和 IL-21 方面存在缺陷。我们进一步证明,SLAM(Slamf1,CD150),一种使用 SAP 信号的表面受体,特异性地需要 GC T(FH)细胞产生 IL-4。GC T(FH)细胞需要产生 IL-4 和 -21 以最佳地辅助 B 细胞。这些数据说明了 SAP 依赖性 SLAM 家族受体信号的复杂性,揭示了 SLAM 受体配体在 GC CD4 T 细胞中产生 IL-4 的重要作用,但在 T(FH)细胞和 GC T(FH)细胞分化中不起作用。
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