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Molecular and cellular basis of Combined Adjuvant-Elicited Cellular Immunity

联合佐剂引发的细胞免疫的分子和细胞基础

基本信息

批准号：
9197094
负责人：
Ross M Kedl
金额：
$ 52.02万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-15 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9197094
关键词：
3-Dimensional Adjuvant Agonist Antibodies Antigens Architecture Attenuated Vaccines Automobile Driving BLR1 gene Bacteria Biological Models Biology CCL3 gene CD4 Positive T Lymphocytes CD8B1 gene CXCR3 gene Cell Communication Cells Cellular Immunity Cellular biology Clinical Data Development Event Future Generations Human Resources ITGAX gene Image Immune Immune response Immune system Immunity Immunization Immunologics Infection Informatics Interleukin-15 Knockout Mice Knowledge Laboratories Lead Life Mediating Memory Methods Modeling Molecular Mus Nature Nuclear Pathway interactions Phase Phenotype Population Primates Process Publishing Qualifying Reporter Role Signal Transduction Subunit Vaccines T cell response T memory cell T-Cell Activation T-Lymphocyte TNFRSF5 gene Testing Thinking Time Toll-like receptors Transgenic Organisms Vaccination Vaccine Adjuvant Vaccines Viral Vector Virus base clinically relevant cytokine genetic signature in vivo innovation insight intravital imaging multi-photon nonhuman primate novel pathogen programs research study response tool transcription factor transcriptome sequencing vaccination strategy vaccine development vaccine response vaccine trial

项目摘要

Project Summary Immunization with antigen in the presence of agonists for both a Toll Like Receptor (TLR) and CD40 (combined TLR/CD40 immunization) elicits a vigorous expansion of antigen-specific CD8+ T cells that is exponentially greater than the response elicited by either agonist alone. Not only is the primary immune response to this vaccination robust, it also forms long lived, CD8+ T cell memory that can protect against future infectious challenge even in the absence of CD4+ T cells. This has been recently verified in non- human primates, where the vaccine produced responses exponentially stronger than responses to typical viral vectors. Given the potency and clinical potential for this vaccine adjuvant platform, it is critical that we understand its molecular and cellular mechanistic underpinnings. We recently made the surprising discovery that T cell responses to this, and related, vaccinations were unexpectedly and completely dependent on two cytokines (IL-27 and IL-15) and two transcription factors (Tbet and Eomes). This was unexpected because the loss of any one of these factors essentially ablates the response to the vaccine but has little to no effect on the response to live virus or bacteria. Thus, the rules behind robust subunit vaccine-elicited immunity appear to be substantially different than those guiding infectious responses. This proposal will use cutting edge methods and approaches to fully understand the nature of this difference and will test i) how IL-27 and IL-15 influence downstream transcriptional and cellular factors, ii) how Tbet and Eomes expression subsequently program T cell activation and expansion, and iii) how these factors mediate T-DC and T-T interactions during the earliest events of T cell activation after combined adjuvant vaccination.

项目总结