T follicular helper memory cells

 描述（申请人提供）：CD4 T滤泡辅助细胞（Tfh）需要为抗原特异性生发中心B细胞反应提供帮助，从而促进抗体的亲和力成熟以及长寿命浆细胞和记忆B细胞的生成。因此，了解Tfh细胞如何发育并发挥其效应功能具有重要意义。 对通过疫苗接种促进抗体介导的传染病预防的兴趣。急性病毒感染后，针对病毒抗原的幼稚 CD4 T 细胞会经历 巨大的变化，包括强劲的增殖以及分化为不同的 T 辅助细胞 1 (Th1) 和 Tfh 细胞谱系。病毒清除后，记忆 Th1 和 Tfh 细胞亚群得以保留，能够在重新暴露于抗原时回忆起其谱系特异性功能。在本研究项目的目标 1 中，我们将研究 CD4 Tfh 效应细胞和记忆细胞在病毒感染与蛋白抗原免疫期间如何分化。我们将确定这些不同类型的免疫反应是否会改变抗原再攻击后 Tfh 和 Th1 记忆细胞的功能和谱系稳定性。我们还将确定用抗原或异源感染重复加强免疫是否会增强 Tfh 和 Th1 谱系定型，或对这些细胞进行重新编程以获得新的表型和功能特征。在该提案的目标 2 中，我们将研究 DNA 甲基化变化介导的表观遗传机制如何调节谱系定型 Tfh 和 Th1 记忆细胞记住其先前编程的效应基因表达的能力，并抑制与其他 T 辅助谱系相关的基因转录。这将通过全基因组甲基化分析、差异甲基化候选基因座的验证以及功能实验来确定细胞在记忆 Tfh 和 Th1 细胞重新激活后是否重新表达未甲基化（稳定）和甲基化（抑制）基因座。最后，我们将探讨在 Tfh 和 Th1 细胞分化过程中是否获得新的 DNA 甲基化程序，以及这种从头甲基化是否影响记忆 CD4 T 细胞的谱系定型。总之，这些研究将为病毒感染和免疫诱导的记忆 CD4 T 细胞的编程提供新的理解，这反过来又将使我们能够指导疫苗介导的反应，以改善针对传染病的持久免疫保护。

 DESCRIPTION (provided by applicant): CD4+ T follicular helper cells (Tfh) cells are required to provide help for antigen-specific germinal center B cell responses, thereby promoting the affinity maturation of antibodies and the generation of long-lived plasma cell and memory B cells. Therefore, understanding how Tfh cells develop and exert their effector function is of great interest for efforts to promote antibody-mediated protection against infectious diseases through vaccination. Following acute viral infection, naïve CD4 T cells specific for viral antigen undergo dramatic changes, including robust proliferation, and differentiation to the distinct T helper 1 (Th1) and Tfh cell lineages. Following clearance of virus, subsets of memory Th1 and Tfh cells are maintained, with the ability to recall their lineage-specific functions upon re-exposure to antigen. In Aim1 of this research project, we will investigate how CD4 Tfh effector and memory cells differentiate during viral infection versus immunization with a protein antigen. We will determine whether these different types of immune reactions alter the function and lineage stability of Tfh and Th1 memory cells upon antigenic rechallenge. We will also determine whether repeated boosting with antigen or heterologous infections reinforces Tfh and Th1 lineage commitment, or reprograms these cells to acquire new phenotypic and functional traits. In Aim 2 of this proposal, we will investigate how epigenetic mechanisms mediated by changes in DNA methylation regulate the ability of lineage-committed Tfh and Th1 memory cells to remember their previously programmed effector gene expression, and repress transcription of genes relevant to other T helper lineages. This will be done using genome-wide methylation analysis, validation of candidate loci that are differentially methylated, and functional experiments to determine whether cells re-express unmethylated (poised) and methylated (repressed) loci upon reactivation of memory Tfh and Th1 cells. Finally, we will explore whether new DNA methylation programs are acquired during Tfh and Th1 cell differentiation, and whether this de novo methylation influences the lineage-commitment of memory CD4 T cells. Together, these studies will provide novel understanding into the programming of virus infection- and immunization-induced memory CD4 T cells, which in turn would allow us to direct vaccine- mediated responses toward improved lasting immune protection against infectious diseases.