Modulating costimulation pathways to improve follicular helper T cell and antibody responses

滤泡辅助性T细胞（TFH）是建立对感染的保护性免疫所必需的 和免疫接种，它们帮助生殖中心（GC）B细胞产生高亲和力抗体， 产生浆细胞和记忆B细胞。因此，TFH-B细胞协同性构成了 疫苗诱导的免疫记忆形成。解读促进TFH细胞生长的途径和因子 分化和功能是配制更有效疫苗的先决条件。 响应于感染或免疫，活化的CD 4 + T细胞经历阶段性分化， 成为功能性的TFH细胞。这些阶段包括早期TFH谱系特化， 产生新生TFH细胞，GC反应阶段成熟为GC-TFH细胞，后期形成记忆 TFH细胞。疫苗以减毒活病毒、灭活生物体或蛋白质亚组分的形式提供 通过不同的路线。是否所有的TFH细胞都是由不同的细胞产生的，这还没有引起足够的注意。 疫苗接种方法。 我们将我们的体内研究扩展到CD 28和ICOS共刺激受体，这是公认的。 TFH调节器。CD 28-PYAP和ICOS-YMFM细胞内基序优先连接至PKCq/PDK 1 和PI 3 K-Akt通路。目前的观点认为，CD 28是启动和ICOS的关键， 维持TFH反应。与此相反，我们的初步数据显示，ICOS-YMFM基序是 CD 28-PYAP基序是启动Inf_TFH所必需的，而CD 28-PYAP基序是维持Inf_TFH所必需的 应答这些发现导致了我们的中心假设，即TFH细胞具有不同的分子 取决于活化剂/方法的要求，其中CD 28和ICOS基序不同， 以阶段特异性方式调节Inf_TFH和Imm_TFH细胞。为了验证这一点，我们设计了多层 3个具体目标的功能和分子研究： 具体目标1。确定TFH命运规范中CD 28和ICOS基序的差异要求。 具体目标2。描绘促进GC-TFH的CD 28和ICOS基序控制的分子回路 细胞成熟和B细胞辅助功能。 具体目标3。探讨CD 28和ICOS基序在记忆TFH持续性和回忆中的作用 反应 因此，开发有效的传染病疫苗对于保护部队至关重要， 服务，以及退伍军人。我们提出的研究直接解决了这一需要，通过推进理解， 在新的领域建立TFH组织我们期望得到关于定制TFH活性的基本信息，以提供最佳的 B细胞的帮助，并因此提供范式转变的原理，以提高疫苗的设计。

T follicular helper (TFH) cells are essential for establishing protective immunity in responses to infection and immunization, where they help high-affinity antibody production by germinal center (GC) B cells, generation of plasma cells and memory B cells. The TFH-B cell cooperativity thus constitutes the cornerstone of immunological memory formation induced by vaccines. Deciphering pathways and factors that promote TFH cell differentiation and function is a prerequisite for formulating more efficacious vaccines. In response to infection or immunization, activated CD4+ T cells undergo stage-wise differentiation to become functionally competent TFH cells. These stages include early stage TFH lineage specification to generate nascent TFH cells, GC response stage to mature to GC-TFH cells, and later stage formation of memory TFH cells. Vaccines are delivered as live-attenuated viruses, inactivated organisms, or protein subcomponents via different routes. It has not drawn enough attention whether all TFH cells are created equal by different vaccination approaches. We extended our in vivo studies to CD28 and ICOS costimulatory receptors, which are well-established TFH regulators. CD28-PYAP and ICOS-YMFM intracellular motifs are preferentially connected to PKCq/PDK1 and PI3K-Akt pathways, respectively. Current views hold that CD28 is critical for initiating and ICOS for sustaining TFH responses. Contrary to this belief, our preliminary data revealed that the ICOS-YMFM motif is essential for initiating Imm_TFH, while the CD28-PYAP motif was indispensable for sustaining Inf_TFH responses. These findings led to our central hypothesis that TFH cells have distinct molecular requirements depending on activating agents/approaches, where CD28 and ICOS motifs differentially regulate Inf_TFH and Imm_TFH cells in a stage-specific manner. To test this, we designed multi-layered functional and molecular studies in 3 specific aims: Specific Aim 1. To define differential requirements for CD28 and ICOS motifs in TFH fate specification. Specific Aim 2. To delineate CD28 and ICOS motif-controlled molecular circuits that promote GC-TFH cell maturation and B-cell help function. Specific Aim 3. To investigate the roles of CD28 and ICOS motifs in memory TFH persistence and recall response. Developing efficacious vaccines against infectious diseases is thus essential for protecting troops in service as well as veterans. Our proposed study directly addresses this need, by advancing the understanding of TFH cells at new frontiers. We expect to yield essential information on tailoring TFH activity to provide optimal B cell help, and hence provide paradigm-shifting rationales for enhancing vaccine design.