Regulation of CD4+ T Cell Responses During Chronic Viral Infection

慢性病毒感染期间 CD4 T 细胞反应的调节

• 批准号: 10322954
• 负责人: Linda Mac Pherson Bradley
• 金额: $ 9.47万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-18 至 2022-11-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10322954
• 关键词: Acute; Adoptive Transfer; Affect; Antibodies; Antigens; Antiviral Response; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Adhesion Molecules; Cell Compartmentation; Cell physiology; Cells; Cellular biology; Chronic; Communicable Diseases; Development; Future; Generations; Genes; Genetic Transcription; Goals; HIV; Helper-Inducer T-Lymphocyte; Hepatitis B Virus; Heterogeneity; Image; Immune checkpoint inhibitor; Immune response; Immunity; Immunodominant Epitopes; Immunologic Memory; Infection; Inflammation; Lead; Lymphocytic choriomeningitis virus; Malignant Neoplasms; Mediating; Memory; Modeling; Morbidity - disease rate; Mus; Mutation; P-selectin ligand protein; Pathogenicity; Play; Population; Recombinants; Regulation; Resolution; Role; Signal Transduction; Spleen; T cell differentiation; T cell response; T-Cell Activation; T-Cell Depletion; T-Lymphocyte; Tamoxifen; Testing; Therapeutic Intervention; Time; Transcriptional Regulation; Transgenic Organisms; Ursidae Family; Vaccine Design; Variant; Virus; Virus Diseases; Wild Type Mouse; acute infection; adaptive immune response; cell motility; chronic infection; congenic; differential expression; effector T cell; exhaust; exhaustion; experimental study; immune checkpoint blockade; improved; improved outcome; inflammatory milieu; innovation; longitudinal analysis; novel; novel strategies; novel therapeutics; pathogen; prevent; programmed cell death protein 1; receptor; response; single cell sequencing; success; therapeutic target; transcriptomics; two photon microscopy

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.

项目摘要 对传染病和癌症的免疫力取决于强大的T细胞应答，以清除病原体或 受损的细胞，并建立记忆种群，以防止未来的挑战。了解T细胞 因此，包括T细胞活化、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。 开发新的疗法来增强这种反应并影响免疫记忆。尽管研究 证明了CD 4+和CD 8 + T细胞对效应子应答和记忆形成的贡献 在病原性感染中，许多人将注意力集中在CD 8 + T细胞区室上，而没有意识到 CD 4 + T细胞的贡献。我们的研究最近发现PSGL-1是一种表达在T细胞上的抑制性受体， 结果表明，PSGL-1的缺失导致CD 4+和CD 8 + T细胞的耗竭减少 在用LCMV克隆13（Cl 13）慢性病毒感染的情况下，在区室中观察到的细胞毒性。这是由能力证明的。 PSGL-1缺陷型小鼠比野生型小鼠更早清除LCMV Cl 13感染。然而，在这方面， 这种清除慢性感染的能力在CD 4 + T细胞耗尽时丧失，这证明了这种能力的重要性。 免疫反应是解决感染所必需的。我们还发现CD 4 + T细胞， 与CD 8 + T细胞一样，对LCMV Armstrong急性感染显示出极大增强的效应子应答， 功能性记忆细胞的持久性更强。本提案中提出的研究目标是进一步 阐明CD 4 + T细胞在急性和慢性感染和记忆产生中的作用， 进一步了解PSGL-1缺陷如何赋予清除感染的能力。为此，贡献 将使用抗原特异性PSGL-1缺陷型CD 4 + T细胞的过继转移来评估PSGL-1缺陷型CD 4 + T细胞 CD 4 + T细胞。由于CD 4 + T细胞群体形成了一个更异质的群体， 随着感染的时间进展，单细胞测序将用于鉴定CD 4 + T细胞的变化。 PSGL-1缺陷型小鼠能够清除LCMV Cl 13，否则LCMV Cl 13会在小鼠中建立慢性感染。 野生型小鼠;发生这种情况的机制将通过研究 PSLG-1缺陷和抗原负荷的影响。由于PSGL-1已被证明影响T细胞活化， 和功能，它代表了改变T细胞分化和记忆形成的治疗靶点;条件性 将在急性和慢性模型中研究PSGL-1信号传导的缺失和抗体介导的调节 进一步阐明PSGL-1在T细胞区室中的作用。这里介绍的研究 提供了一种了解PSGL-1信号调节如何增强T细胞功能和记忆的方法 产生和对CD 4 +T细胞增强CD 8 + T细胞应答的能力的影响， 感染和癌症的背景以及疫苗设计，以提高整体免疫力。