权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Immune function and mechanism of Tim3 expression and Tim3+ T cells in TB & HIV+TB

Tim3表达和Tim3 T细胞在结核病中的免疫功能及机制

基本信息

批准号：
8721335
负责人：
Zheng W Chen
金额：
$ 20万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-15 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8721335
关键词：
Adoptive Transfer Antibodies Antitubercular Agents Attenuated CD3 Antigens CD8B1 gene Cell physiology Cells Chronic Communicable Diseases Depressed mood Down-Regulation Effector Cell Exhibits Galactose Binding Lectin HIV HIV-1 Hepatitis C Host Defense Human Immune Immune response Immunity Immunoglobulins Infection Inflammation Interferons Lesion Ligands MAPK14 gene Macaca Membrane Membrane Proteins Memory MicroRNAs Molecular Mucins Mus Mycobacterium tuberculosis Pathology Pathway interactions Patients Phenotype Play Production Regulation Role Signal Pathway Signal Transduction Signaling Molecule Small Interfering RNA T cell response T-Lymphocyte T-Lymphocyte Subsets TNF gene Testing Th1 Cells Tuberculosis base crosslink cytokine exhaustion immune function immunopathology novel public health relevance research study tuberculosis immunity

项目摘要

DESCRIPTION (provided by applicant): While T cells play a role in host defense against Mycobacterium tuberculosis (Mtb) infection, over-reacting T cell responses may contribute to tuberculosis (TB) inflammation and lesions. It is, therefore, important to characterize immune regulation and function of T cell responses in TB. T cell immunoglobulin and mucin domain-containing molecule 3 (Tim-3) is a membrane protein initially identified as a negative regulator of Th1 cells. However, new studies suggest that Tim-3 expression/ functions in infections appear to be more diverse than previously thought. We have recently found that active TB in macaques and humans remarkably up- regulated Tim-3 expression and that Tim-3+ CD4+/CD8+ T cells displayed polarized effector memory phenotypes. Tim-3+ CD4+/CD8+ T cell subsets showed greater effector functions for producing Th1/Th22/CTL cytokines and for inhibiting intracellular Mtb than Tim-3- T cells. Tim-3+ CD4+/CD8+ T cell subsets are more activated as they expressed much higher levels of phosphorylated signaling molecules p38, stat3, stat5, and Erk1/2 than Tim-3- controls. Silencing of Tim-3 pathway reduced T cell effector function in TB, and stimulation of Tim-3 augmented T effector functions. Our novel findings implicate a new paradigm that Tim-3 signaling facilitates stronger effector functions in active TB patients. We also found that PD-1+ and PD-1- T cells expressed distinct miRNA signatures, and down-regulation of human miRNA miR-31 in PD-1+ T cells enforces stronger effector functions during active TB. Since large numbers of CD4+ and CD8+ T cells express Tim-3 in infections, it is critical to determine whether Tim-3+ CD4+/CD8+ T cells are protective or detrimental, and functional mechanisms. We hypothesize that selected miRNAs help to control or regulate effector functions of Tim-3+ CD4+ and CD8+ T cells in human TB or HIV+TB, and that Tim-3+ T cell effector cells may have double-edge function contributing to both anti-TB immunity and over-reactive immune pathology for TB inflammation and lesions. Our specific aims are: Aim I. Determine if selected miRNAs in Tim-3+ T cells control or regulate effector functions of Tim- 3+ CD4+/CD8+ T cells in active human TB. Aim II. Investigate if selected miRNA signatures in HIV-1 infection potentially depress anti-TB effector functions of Tim-3+ CD4+/CD8+ T cells in HIV+ TB. Aim III. Examine if r-galectin-9 administration during chronic TB can reduce or deplete Tim-3+ CD4+/CD8+ T cells and attenuate immunopathology and TB lesions in macaques. Aim IV. Determine if rapid increases in Tim-3+ T effector cells by adoptive transferring of Tim-3+ T cells during early Mtb infection can confer immune protection against TB in macaques.