Tim-3-Expressing CD4+ and CD8+ T Cells in Human Tuberculosis (TB) Exhibit Polarized Effector Memory Phenotypes and Stronger Anti-TB Effector Functions

PLoS Pathogens

Jianbo Chen¹  Kaiyuan Cao¹  Jiye Cai²  Dan Huang²  Yanfen Luo³  Danyun Fang³  Gucheng Zeng³  Lifang Jiang³  Guobao Li³  Zheng W. Chen³  Yueqin Qiu³  Shaoyuan Li⁴  Boping Zhou⁵  Yan Zhang⁶  Hongying Liao⁷  Crystal Y. Chen⁸  Hua Wang⁹  Ling Shen^1,10 

[1] College of Life Sciences, Jinan University, Guangzhou, China;Department of Microbiology and Immunology, Center for Primate Biomedical Research, University of Illinois College of Medicine, Chicago, Illinois, United States of America;Department of Microbiology, Zhongshan School of Medicine, Key Laboratory for Tropical Diseases Control of the Ministry of Education, Sun Yat-sen University, Guangzhou, China;Department of Oral and Maxillofacial Surgery, Hospital of Stomotology, Guanghua School of Stomotology, Sun Yat-sen University, Guangzhou, China;Department of Pulmonary Diseases, Shenzhen Third People's Hospital, Shenzhen, China;Department of Thoracic Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China;Division of Infection and Immunity, Department for Clinical Microbiological Assays, Shenzhen Third People's Hospital, Shenzhen, China;Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America;Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China;Shenzhen Institute of Hepatology, Shenzhen Third People's Hospital, Shenzhen, China

关键词: T cells;    Cytotoxic T cells;    Mycobacterium tuberculosis;    Tuberculosis;    Flow cytometry;    Cytokines;    Memory T cells;    Cell staining;   

DOI  :  10.1371/journal.ppat.1002984

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

T-cell immune responses modulated by T-cell immunoglobulin and mucin domain-containing molecule 3 (Tim-3) during Mycobacterium tuberculosis (Mtb) infection in humans remain poorly understood. Here, we found that active TB patients exhibited increases in numbers of Tim-3-expressing CD4+ and CD8+ T cells, which preferentially displayed polarized effector memory phenotypes. Consistent with effector phenotypes, Tim-3+CD4+ and Tim-3+CD8+ T-cell subsets showed greater effector functions for producing Th1/Th22 cytokines and CTL effector molecules than Tim-3− counterparts, and Tim-3-expressing T cells more apparently limited intracellular Mtb replication in macrophages. The increased effector functions for Tim-3-expressing T cells consisted with cellular activation signaling as Tim-3+CD4+ and Tim-3+CD8+ T-cell subsets expressed much higher levels of phosphorylated signaling molecules p38, stat3, stat5, and Erk1/2 than Tim-3- controls. Mechanistic experiments showed that siRNA silencing of Tim-3 or soluble Tim-3 treatment interfering with membrane Tim-3-ligand interaction reduced de novo production of IFN-γ and TNF-α by Tim-3-expressing T cells. Furthermore, stimulation of Tim-3 signaling pathways by antibody cross-linking of membrane Tim-3 augmented effector function of IFN-γ production by CD4+ and CD8+ T cells, suggesting that Tim-3 signaling helped to drive stronger effector functions in active TB patients. This study therefore uncovered a previously unknown mechanism for T-cell immune responses regulated by Tim-3, and findings may have implications for potential immune intervention in TB.

【 授权许可】

CC BY