Regulation of CD4+ T cell responses during chronic viral infection

项目总结 对传染病和癌症的免疫力依赖于强大的T细胞反应来清除病原体或 并建立一个记忆群体，以防止未来的挑战。了解T细胞 因此，包括T细胞激活、分化和记忆形成在内的生物学可以指导未来对T细胞的研究 开发新的治疗方法来增强这种反应并影响免疫记忆。虽然研究 证明CD4和CD8T细胞对效应器反应和记忆形成的贡献 在病原性感染中，许多人专注于CD8 T细胞亚群，而没有意识到 CD4T细胞的贡献(S)。我们最近的研究发现PSGL-1是一种表达在T细胞上的抑制性受体 结果表明，PSGL-1的缺失可以减少CD4和CD8T细胞的耗竭 在慢性病毒感染LCMV克隆13(Cl13)的背景下的隔间。这一点可以从以下能力中得到证明 与野生型小鼠相比，PSGL-1缺陷小鼠清除LCMV Cl13感染的时间要早得多。然而， 这种清除慢性感染的能力在CD4T细胞耗尽时就会消失，这表明了这一点的重要性 人群中的免疫反应是化解感染所必需的。我们还发现，CD4T细胞， 像CD8 T细胞一样，对急性感染LCMV阿姆斯特朗的效应器反应大大增强， 功能存储单元的持久性更强。本提案中提出的研究的目标是进一步 阐明CD4T细胞在急、慢性感染和记忆生成中的作用(S) 进一步了解PSGL-1缺乏如何赋予清除感染的能力。为此，所作的贡献 PSGL-1缺陷的CD4T细胞的过继转移将使用抗原特异性PSGL-1缺陷的过继转移进行评估 CD4T细胞。随着CD4T细胞群体形成更多的异质性群体，这一已知的变化 随着感染的时间进展，单细胞测序将被用来识别CD4T细胞的变化。 PSGL-1缺陷小鼠能够清除LCMV Cl13，否则LCMV Cl13会在 野生型小鼠；发生这种情况的机制(S)将通过研究运动性的变化来询问 PSLG-1缺乏症与抗原负荷的影响。由于PSGL-1已被证明影响T细胞激活 和功能，它代表了改变T细胞分化和记忆形成的治疗靶点；有条件的 将在急性和慢性模型中研究PSGL-1信号的缺失和抗体介导的调节 进一步阐明PSGL-1在T细胞亚群中的作用。这里介绍的研究 提供了一种理解PSGL-1信号的调制如何增强T细胞功能和记忆的方法 CD4T细胞增强CD8T细胞应答能力的产生及对其的影响 关于感染和癌症的背景以及疫苗设计以提高整体免疫力。

PROJECT SUMMARY Immunity to infectious disease and cancer is dependent on a robust T cell response to clear the pathogen or compromised cells and establish a memory population to protect against future challenge. Understanding T cell biology including T cell activation, differentiation, and memory formation can thus guide future studies on the development of novel therapies to augment this response and impact immunological memory. Although studies demonstrate the contributions of both CD4+ and CD8+ T cells to the effector response and memory formation with pathogenic infection, many are focused on the CD8+ T cell compartment and fail to appreciate the contribution(s) of CD4+ T cells. Our studies recently identified PSGL-1 as an inhibitory receptor expressed on T cells and showed that deletion of PSGL-1 led to reduced exhaustion in both the CD4+ and CD8+ T cell compartments in the context of chronic virus infection with LCMV clone 13 (Cl13). This is evidenced by the ability of PSGL-1-deficient mice to clear LCMV Cl13 infection much earlier than their wildtype counterparts. However, this ability to clear the chronic infection is lost upon CD4+ T cell depletion, demonstrating the importance of this population in the immune response necessary for the resolution of infection. We also found that CD4+ T cells, like CD8+ T cells, display greatly enhanced effector responses to acute infection with LCMV Armstrong, with greater persistence of functional memory cells. The goal of the studies presented in this proposal is to further elucidate the contribution(s) of CD4+ T cells in both acute and chronic infection and memory generation and to further understand how PSGL-1-deficiency confers the capability to clear infection. To this end, the contribution of PSGL-1 deficient CD4+ T cells will be assessed using adoptive transfer of antigen-specific PSGL-1 deficient CD4+ T cells. As the CD4+ T cells population forms a more heterogenous population that is known to change with the temporal progression of infection, single-cell sequencing will be used to identify changes in CD4+ T cells. PSGL-1-deficient mice are capable of clearing LCMV Cl13 which otherwise establishes a chronic infection in wildtype mice; the mechanism(s) by which this occurs will be interrogated by studying changes in motility with PSLG-1-deficiency and the impact of antigen load. As PSGL-1 has been demonstrated to affect T cell activation and function, it represents a therapeutic target for altering T cell differentiation and memory formation; conditional deletion and antibody mediated modulation of PSGL-1 signaling will be studied in both acute and chronic models of infection to further elucidate the role PSGL-1 plays in the T cell compartment. The studies presented here offer a means to understand how modulation of PSGL-1 signaling could augment T cell function and memory generation and impact on the ability of CD4+T cells to augment CD8+ T cell responses that could be used in context of infection and cancer as well as vaccine design to improve overall immunity.