title: Tim-3-expressing CD4+ and CD8+ T cells in human tuberculosis (TB) exhibit polarized effector memory phenotypes and stronger anti-TB effector functions.
abstract: 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.
authors.affiliation: Department of Microbiology, Zhongshan School of Medicine, Key Laboratory for Tropical Diseases Control of the Ministry of Education, Sun Yat-sen University, Guangzhou, China ; College of Life Sciences, Jinan University, Guangzhou, China.
authors.forename: Yueqin
authors.initials: Y
authors.lastname: Qiu
authors.forename: Jianbo
authors.initials: J
authors.lastname: Chen
authors.forename: Hongying
authors.initials: H
authors.lastname: Liao
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Hua
authors.initials: H
authors.lastname: Wang
authors.forename: Shaoyuan
authors.initials: S
authors.lastname: Li
authors.forename: Yanfen
authors.initials: Y
authors.lastname: Luo
authors.forename: Danyun
authors.initials: D
authors.lastname: Fang
authors.forename: Guobao
authors.initials: G
authors.lastname: Li
authors.forename: Boping
authors.initials: B
authors.lastname: Zhou
authors.forename: Ling
authors.initials: L
authors.lastname: Shen
authors.forename: Crystal Y
authors.initials: CY
authors.lastname: Chen
authors.forename: Dan
authors.initials: D
authors.lastname: Huang
authors.forename: Jiye
authors.initials: J
authors.lastname: Cai
authors.forename: Kaiyuan
authors.initials: K
authors.lastname: Cao
authors.forename: Lifang
authors.initials: L
authors.lastname: Jiang
authors.forename: Gucheng
authors.initials: G
authors.lastname: Zeng
authors.forename: Zheng W
authors.initials: ZW
authors.lastname: Chen
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology*; D000072597:Hepatitis A Virus Cellular Receptor 2; D006801:Humans; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D008565:Membrane Proteins / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology*; D014376:Tuberculosis / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; C573415:IFNG protein, human; D008565:Membrane Proteins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma