Follicular helper CD4+ T-cells (Tfh) control humoral immunity by driving affinity maturation and isotype-switching of activated B-cells. Tfh localize within B-cell follicles and, upon encounter with cognate antigen, drive B-cell selection in germinal centers (GCs) as GC-Tfh. Tfh functionality is controlled by Foxp3-expressing Tfh, which are known as regulatory T follicular cells (Tfr). Thus far, it remains unclear which factors determine the balance between these functionally opposing follicular T-cell subsets. Here, we demonstrate in human and mouse that Tfh and GC-Tfh, as well as their regulatory counterparts, express glucocorticoid-induced TNF receptor related protein (GITR) on their surface. This costimulatory molecule not only helps to identify follicular T-cell subsets, but also increases the ratio of Tfh vs. Tfr, both within and outside the GC. Correspondingly, GITR triggering increases the number of IL-21 producing CD4+ T-cells, which also produce more IFN-γ and IL-10. The latter are known switch factors for IgG2c and IgG1, respectively, which corresponds to a concomitant increase in IgG2c and IgG1 production upon GITR-mediated costimulation. These results demonstrate that GITR can skew the functional balance between Tfh and Tfr, which offers new therapeutic possibilities in steering humoral immunity.

中文翻译：

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GITR通过控制卵泡T辅助细胞和调节性T卵泡细胞之间的平衡来塑造体液免疫。

滤泡辅助CD4 + T细胞（Tfh）通过驱动活化B细胞的亲和力成熟和同种型转换来控制体液免疫。Tfh定位在B细胞滤泡中，一旦遇到同源抗原，就会驱动生发中心（GCs）中的B细胞选择为GC-Tfh。Tfh功能由表达Foxp3的Tfh（称为调节性T滤泡细胞（Tfr））控制。到目前为止，还不清楚哪些因素决定这些功能相反的滤泡性T细胞亚群之间的平衡。在这里，我们在人和小鼠中证明了Tfh和GC-Tfh以及它们的调节对应物在其表面表达糖皮质激素诱导的TNF受体相关蛋白（GITR）。这种共刺激分子不仅有助于识别卵泡T细胞亚群，还可以提高Tfh与Tfr的比率，在GC内部和外部。相应地，GITR触发增加了产生IL-21的CD4 + T细胞的数量，后者也产生了更多的IFN-γ和IL-10。后者分别是IgG2c和IgG1的已知转换因子，其对应于GITR介导的共刺激时IgG2c和IgG1产生的同时增加。这些结果表明，GITR可以扭曲Tfh和Tfr之间的功能平衡，从而为指导体液免疫提供新的治疗可能性。