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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结