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

描述（由申请人提供）：CD 8 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。CD 8 T细胞介导的免疫应答由几个不同的阶段组成，包括抗原特异性初始CD 8 T细胞的活化、效应CD 8 T细胞的克隆扩增和记忆CD 8 T细胞的形成。在效应CD 8 T细胞中，KLRG 1 +IL-7 R <$-细胞被认为是终末分化的细胞溶解效应细胞，KLRG 1 loIL-7 R <$+细胞具有增加的产生持久记忆CD 8 T细胞的潜力，并被认为是记忆前体。在记忆性CD 8 T细胞中，CD 62 L+中枢记忆性T细胞在稳态自我更新和次级增殖中比CD 62 L-效应记忆性T细胞更有效。 已知T细胞因子1（TCF 1）转录因子介导经典Wnt信号传导，并且在T细胞发育中起重要作用。近年来，我们和其他人的研究发现了它在调节成熟CD 8 T细胞应答中的新兴作用。具体而言，CD 8 T细胞中Wnt信号传导途径的激活足以扩增记忆性CD 8 T细胞库。此外，在迄今为止研究的CD 8 T细胞应答中的所有转录因子中，TCF 1缺乏最严重地损害了中央记忆T细胞成熟、记忆T细胞持久性和次级扩增。我们的初步研究进一步揭示，尽管TCF 1在KLRG 1 +IL-7 R效应T细胞中显著下调，但TCF 1的大量表达在KLRG 1 loIL-7 R+记忆前体细胞和CD 62 L+中央记忆细胞中保留。此外，TCF 1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TCF 1在CD 8 T细胞应答过程中控制独特的转录程序，并且TCF 1及其下游基因在CD 8效应子中的保留有利于记忆前体的分化和自我更新中枢记忆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：具体目标1。阐明TCF 1在CD 8 T细胞应答中调控的基因调控回路。具体目标2。确定TCF 1下游基因，促进记忆前体和中央记忆T细胞的产生。通过这些拟议的研究，我们将实现的是阐明TCF 1控制的基因调控程序的分子布线，并确定其在促进产生稳健和持久的记忆性CD 8 T细胞中的功能重要性。这些系统的方法可能会导致发现的关键决定因素指导CD 8效应记忆的命运。该项目将对设计利用Wnt衍生信号或其分子靶点来改善疫苗/佐剂设计的策略产生重大影响，旨在增强针对感染因子和恶性细胞的T细胞免疫力。

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.