Delineate common cellular circuits that orchestrate T cell immunity in chronic infections and tumors

在免疫反应失败的情况下重新唤醒T细胞介导的免疫已经取得了巨大的成功，并为治疗慢性感染或肿瘤患者带来了重大的希望。两者都诱导功能失调的病毒特异性CD8 T细胞，称为T细胞耗竭。终末耗竭的T细胞，其特征在于增殖能力下降和效应分子的产生以及共抑制受体的持续表达，对免疫检查点阻断是难治的。T细胞耗竭构成免疫治疗的主要限制因素，但从进化的角度来看，它是一个关键过程，已经进化到限制慢性感染中的免疫病理学与持续的病毒产生。此外，新兴的工作揭示了表达转录因子T细胞因子1（TCF 1）的病毒特异性CD8+ T细胞的独特亚群，称为祖细胞耗竭的T细胞，显示干细胞样表型，并表现出稳健的增殖和分化为效应CD8+ T细胞。这些细胞构成免疫疗法诱导的抗肿瘤和抗病毒应答的起点。然而，目前尚不清楚哪些细胞和分子因素可以将干细胞样CD8耗尽的T细胞形成为可以产生的各种亚群，以及我们是否可以更有效地利用潜在的调节来增强抗病毒T细胞应答。在这里，我们的目标是阐明详细的分子和细胞之间的串扰DC，包括pDC和传统的I型树突状细胞（cDC1），和CD8 T细胞在慢性感染，并进一步研究如何CD4 T细胞可以微调这一过程，以指导宿主的抗病毒免疫慢性病毒感染。这种专门的串扰的知识可以作为一个跳板，以扩大我们的视野细胞和分子机制，指导CD8 T细胞分化在慢性抗原暴露的情况下。

Reawakening T cell-mediated immunity in cases of failed immunoptorection has been tremendously successful and holds significant promises for treating patients with chronic infection or tumors. Both induce dysfunctional virus-specific CD8 T cells known as T cell exhaustion. Terminally exhausted T cells, characterized by declined proliferative capacity and production of effector molecules and sustained expression of co-inhibitory receptors, are refractory to immune checkpoint blockade. T cell exhaustion constitute a major limiting factor for immunotherapy but it is from an evolutionary perspective a key process which has evolved to restrict immunopathology in chronic infection with sustained virus production. In addition, emerging works reveal that a unique subset of virus-specific CD8+ T cells expressing the transcription factor T-cell factor 1 (TCF1), referred as progenitor exhausted T cells, display a stem-like phenotype and exhibit robust proliferation and differentiation into effector CD8+ T cells. These cells constitute a starting point for immunotherapy induced anti-tumor and anti-viral responses. However, it remains unclear which cellular and molecular factors could orchestrate the formation of stem-like CD8 exhausted T cells into the various subsets that can generate and whether we could more effectively exploit the underlying regulations to augment anti-viral T cell responses. Here, we aim to elucidate the detailed molecular and cellular crosstalk between DCs, including pDCs and conventional type I dendritic cells (cDC1s), and CD8 T cells in chronic infection and further investigate how CD4 T cells can fine-tune this process to guide host anti-viral immunity in chronic viral infection. Knowledge of such specialized crosstalk can serve as a springboard to broaden our horizon on cellular and molecular machineries that guiding CD8 T cell differentiation in chronic antigen exposure contexts.