Decoding TCF1-controlled transcriptional program that promotes memory T cell fate

描述（由申请人提供）：CD8 T细胞在控制细胞内病原体（包括病毒和细胞内细菌）感染方面至关重要。CD8 T细胞介导的免疫应答包括几个不同的阶段，包括抗原特异性特异性CD8 T细胞的激活、效应CD8 T细胞的克隆扩增和记忆性CD8 T细胞的形成。在CD8 T效应细胞中，KLRG1+IL-7R -细胞被认为是终末分化的细胞溶解效应细胞，KLRG1+IL-7R -细胞具有增加产生持久记忆CD8 T细胞的潜力，被认为是记忆前体。在记忆性CD8 T细胞中，CD62L+中枢记忆T细胞比CD62L-效应记忆T细胞在稳态自我更新和二次增殖方面更有效。已知T细胞因子1 （TCF1）转录因子介导典型Wnt信号传导并在T细胞发育中发挥重要作用。近年来，我们等人的研究发现了它在调节成熟CD8 T细胞反应中的新作用。具体来说，激活CD8 T细胞中的Wnt信号通路足以扩大记忆性CD8 T细胞池。此外，在迄今为止研究的所有与CD8 T细胞应答相关的转录因子中，TCF1缺陷对中枢记忆T细胞成熟、记忆T细胞持久性和继发性扩增的影响最为严重。我们的初步研究进一步发现，尽管TCF1在KLRG1+IL-7R效应T细胞中显著下调，但在klrg1oil - 7r +记忆前体和CD62L+中枢记忆细胞中仍大量表达TCF1。此外，TCF1的缺失大大降低了效应期记忆前体的频率。基于这些发现，我们假设TCF1在CD8 T细胞应答过程中控制着独特的转录程序，而TCF1及其下游基因在CD8效应物中的保留有利于记忆前体的分化和自我更新的中央记忆T细胞的形成。我们建议通过以下具体目标来检验这一假设：阐明tcf1调控的基因调控回路在CD8 T细胞反应中的作用。具体目标2。鉴定促进记忆前体和中枢记忆T细胞产生的TCF1下游基因。通过这些拟议的研究，我们将实现的是阐明tcf1控制的基因调控程序的分子连接，并确定其在促进生成稳健和持久记忆的CD8 T细胞中的功能重要性。这些系统的方法可能会导致发现指导CD8效应物进入记忆命运的关键决定因素。该项目将对设计利用Wnt衍生信号或其分子靶点来改进疫苗/佐剂设计的策略产生重大影响，旨在增强T细胞对传染性病原体和恶性细胞的免疫力。

DESCRIPTION (provided by applicant): CD8 T cells are critical in controlling infection by intracellular pathogens including viruses and intracellular bacteria. CD8 T cell-mediated immune responses consist of several distinct stages, including activation of antigen-specific na¿ve CD8 T cells, clonal expansion of effector CD8 T cells, and formation of memory CD8 T cells. Among effector CD8 T cells, the KLRG1+IL-7R¿- cells are considered to be terminally differentiated cytolytic effectors, and KLRG1loIL-7R¿+ cells have increased potential to give rise to long-lasting memory CD8 T cells and deemed to be memory precursors. Among memory CD8 T cells, CD62L+ central memory T cells are more efficient in homestatic self-renewal and secondary proliferation than CD62L- effector memory T cells. The T cell factor 1 (TCF1) transcription factor is known to mediate the canonical Wnt signaling and play important roles in T cell development. In recent years, studies by us and others discovered its emerging roles in regulating mature CD8 T cell responses. Specifically, activation of the Wnt signaling pathway in CD8 T cells was sufficient to expand the memory CD8 T cell pool. Furthermore, among all the transcription factors that have been studied in CD8 T cell responses to date, TCF1 deficiency most profoundly impaired central memory T cell maturation, memory T cell persistence and secondary expansion. Our preliminary studies further revealed that albeit TCF1 was significantly downregulated in KLRG1+IL-7R¿- effector T cells, substantial expression of TCF1 was retained in KLRG1loIL-7R¿+ memory precursors and CD62L+ central memory cells. In addition, loss of TCF1 greatly diminished the frequency of memory precursors at the effector phase. Based on these findings, we hypothesize that TCF1 controls unique transcriptional programs during CD8 T cell responses and retention of TCF1 and its downstream genes in CD8 effectors favors differentiation of memory precursors and formation of self-renewing central memory T cells. We propose to test this hypothesis through the following specific aims: Specific Aim 1. To elucidate the TCF1-regulated gene regulatory circuits throughout the CD8 T cell responses. Specific Aim 2. To identify TCF1 downstream genes that promote generation of memory precursors and central memory T cells. Through these proposed studies, what we will achieve is to elucidate the molecular wiring of TCF1-controlled gene regulatory program and determine its functional importance in promoting generation of robust and long- lasting memory CD8 T cells. These systematic approaches may lead to discovery of key determinants directing CD8 effectors to a memory fate. This project will have a major impact on devising strategies to utilize Wnt- derived signals or their molecular targets to improve vaccine/adjuvant design, aiming for enhanced T cell immunity against infectious agents and malignant cells.