Rolf Julia, Bell Sarah E, Kovesdi Dorottya, Janas Michelle L, Soond Dalya R, Webb Louise M C, Santinelli Sara, Saunders Ted, Hebeis Barbara, Killeen Nigel, Okkenhaug Klaus, Turner Martin
Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge, United Kingdom.
J Immunol. 2010 Oct 1;185(7):4042-52. doi: 10.4049/jimmunol.1001730. Epub 2010 Sep 8.
The generation of high-affinity Abs is essential for immunity and requires collaboration between B and T cells within germinal centers (GCs). By using novel mouse models with a conditional deletion of the p110δ catalytic subunit of the PI3K pathway, we established that p110δ is required in T cells, but not in B cells, for the GC reaction. We found the formation of T follicular helper (T(FH)) cells to be critically dependent on p110δ in T cells. Furthermore, by deleting phosphatase and tensin homolog deleted on chromosome 10, which opposes p110δ in activated T cells, we found a positive correlation between increased numbers of T(FH) cells and GC B cells. These results are consistent with the hypothesis that T cell help is the limiting factor in the GC reaction. P110δ was not required for the expression of B cell lymphoma 6, the downregulation of CCR7, or T cell entry into primary follicles. Instead, p110δ was the critical catalytic subunit for ICOS downstream signaling and the production of key T(FH) cytokines and effector molecules. Our findings support a model in which the magnitude of the GC reaction is controlled by the activity of the PI3K pathway in T(FH) cells.
高亲和力抗体的产生对免疫至关重要，并且需要生发中心（GCs）内的B细胞和T细胞之间协作。通过使用新型小鼠模型，条件性删除PI3K途径的p110δ催化亚基，我们证实GC反应需要T细胞而非B细胞中的p110δ。我们发现T滤泡辅助（T(FH)）细胞的形成严重依赖于T细胞中的p110δ。此外，通过删除在活化T细胞中与p110δ拮抗的10号染色体上缺失的磷酸酶和张力蛋白同源物，我们发现T(FH)细胞数量增加与GC B细胞之间存在正相关。这些结果与T细胞辅助是GC反应中的限制因素这一假设一致。B细胞淋巴瘤6的表达、CCR7的下调或T细胞进入初级滤泡并不需要p110δ。相反，p110δ是ICOS下游信号传导以及关键T(FH)细胞因子和效应分子产生的关键催化亚基。我们的研究结果支持一种模型，即GC反应的强度由T(FH)细胞中PI3K途径的活性控制。
