生发中心（germinal center，GC）是形成高亲和力、长效体液免疫的关键。其中GC B细胞通过交替于在暗区快速增殖伴随BCR突变和在明区争夺抗原伴随亲和力筛选这两种状态，最终形成长效浆细胞和GC依赖性记忆B细胞。通常来说，生发中心反应依赖于一类特殊的CD4+ T细胞亚群被称作滤泡辅助性T细胞（follicular helper T cell，TFH），TFH细胞可以为GC B细胞提供各类帮助信号。T细胞招募进入滤泡区的过程依赖能响应滤泡区趋化因子的CXCR5受体和ICOS。其中ICOS介导的T细胞运动依赖于PI3K通路的活性和滤泡区抗原非特异性初始B细胞上持续表达的ICOSL。然而，ICOS信号对T细胞在T细胞区的运动并不是必须的，暗示滤泡区微环境可能为T细胞的迁移深入设置了抑制性环境，从而需要ICOS信号解除该抑制。在本文中我检测了PD-1作为该抑制信号限制T细胞进入滤泡区的可能性。PD-1在T细胞活化后被迅速上调，并且滤泡区初始B细胞持续高表达配体PD-L1。在TCR信号缺失的情况下，单独刺激PD-1即可在体外抑制CXCR5或ICOS诱导的PI3K活性；而PD-1过表达的T细胞在体内显示出向滤泡区归巢的缺陷。通过利用T细胞活化后无法上调PD-1表达的Pdcd1KI/KI敲除小鼠，我进一步展示了抑制PD-1的上调可以拯救ICOS信号缺失下T细胞向滤泡区招募的缺陷。因此，在TFH形成过程中，特异性地在T-B交界区需要ICOS信号来解除PD-1介导的PI3K抑制，从而帮助T细胞进入滤泡区。虽然ICOS和PD-1看似在调控TFH细胞分化的过程中是一对相互拮抗的分子，但是TFH需要同时高表达这两个分子才能完整地执行其功能。定位于滤泡和GC区域的TFH细胞通过传递细胞间相互作用依赖的信号和分泌型因子调控GC B细胞的行为，包括B细胞的分化命运决定。通过对近期鉴定出的GC依赖性记忆B细胞前体细胞（GC-derived memory B cell precursor，GCMP）进行基因表达谱分析，我们发现GCMP细胞高表达白介素-9受体（IL-9R）并且可以响应IL-9信号。在体内快速处理IL-9或IL-9中和抗体可以促进或削弱GCMP的形成，加快或减慢GCMP向GC边缘移动，以及增加和减少记忆B细胞的输出。而在GC反应中，IL-9主要来源于TFH细胞。T细胞，或者更精确的TFH细胞缺失IL-9均会导致记忆B细胞生成的缺陷。因此，TFH细胞通过分泌IL-9来调控GC B细胞向记忆B细胞的分化。

Germinal centers (GCs) support the generation of high-affinity, long-lived humoral immunity. GC B cells undergo cyclic alternation between proliferation and antigen-receptor hypermutation in the dark zone (DZ) and antigen acquisition and selection in the light zone (LZ), and eventually give rise to long-lived plasma cells and GC-dependent memory B cells. Follicular helper T (TFH) cells, a specialized CD4+ effector T-cell subset, deliver soluble and contact-dependent signals to B cells and are necessary for driving the GC reaction.The follicular recruitment of T cells depends on follicle-sensing chemokine receptor CXCR5 and costimulatory molecule ICOS, which can stimulate T-cell motility in a PI3K-dependent manner. Interestingly, this motility-driving effect of ICOS requires follicular bystander B cells that do not present cognate antigen but constitutively express ICOSL. However, ICOS is not required for T-cell motility in the T-cell zone, implying the follicular niche may be an inhibitory environment for T-cell migration and TFH cells must overcome such inhibition with ICOS signaling. Here I address the hypothesis that PD-1 is an motility-inhibitory factor limiting the follicular recruitment of T cells. PD-1 is rapidly upregulated on T cells following activation and whose ligand is constitutively expressed by follicular B cells. I show that in the absence of TCR triggering, PD-1 signaling antagonizes PI3K activities triggered by CXCR5 or ICOS in vitro, while PD-1 overexpression suppresses follicular recruitment in vivo. Using a knock-in mutant Pdcd1 allele (Pdcd1KI/KI) that abrogates PD-1 upregulation on activated T cells, I further show that subdued PD-1 induction rescues the impaired follicular recruitment due to the ICOS deficiency of T cells or the ICOSL deficiency of bystander B cells. Therefore, ICOS is required in part to counteract PD-1-mediated inhibition of PI3K activities and follicular recruitment. Despite of the paradoxically antagonism between ICOS and PD-1 in the migration of T cells, TFH cells need both of them to be fully functional.Follicle- and GC-localized TFH cells deliver contact-dependent and soluble factors to regulate GC B cell behaviors, likely including post-GC fate choice. By profiling newly identified CD38+GL7+FAS+BCL-6lo GC-derived memory B cell precursors (GCMP) and compared to CD38-GL7+FAS+BCL-6hi GC B cells that are also not dividing, we show that GCMP cells express higher levels of the Interleukin-9 (IL-9) receptor and respond to IL-9. Acute IL-9 or anti-IL-9 treatment in vivo induces changes consistent with promotion or impairment of GCMP formation, accelerates or retards GCMP positioning toward the GC edge and output, and enhances or inhibits the development of memory B cells. During ongoing GC responses, memory development requires B cell-intrinsic responsiveness to IL-9, while TFH cells produce IL-9. IL-9 deletion from T cells, or more specifically from GC TFH cells, leads to impaired memory B cell formation. Together, our results identify TFH-derived IL-9 as a key factor in promoting GC development of memory B cells.