title: Selective Destruction of Interleukin 23-Induced Expansion of a Major Antigen-Specific γδ T-Cell Subset in Patients With Tuberculosis.
abstract: A loss of antigen-specific T-cell responses due to defective cytokine signaling during infections has not been reported. We hypothesize that tuberculosis can destroy signaling effects of selective cytokine(s) and induce exhaustion of antigen-specific T cells. To test this hypothesis, mechanistic studies were performed to examine whether and how tuberculosis blocked interleukin 23 (IL-23) and interleukin 2 (IL-2) signaling effects on a major human γδ T-cell subpopulation, phosphoantigen HMBPP-specific Vγ2Vδ2 T cells. IL-23 and IL-2 significantly expanded HMBPP-stimulated Vγ2Vδ2 T cells from subjects with latent tuberculosis infection, and IL-2 synergized the effect of IL-23. IL-23-induced expansion of Vγ2Vδ2 T cells involved STAT3. Surprisingly, patients with tuberculosis exhibited a selective destruction of IL-23-induced expansion of these cells. The tuberculosis-driven destruction of IL-23 signaling coincided with decreases of expression and phosphorylation of STAT3. Interestingly, impairing of STAT3 was linked to marked increases in the microRNAs (miRNAs) hsa-miR-337-3p and hsa-miR-125b-5p in Vγ2Vδ2 T cells from patients with tuberculosis. Downregulation of hsa-miR-337-3p and hsa-miR-125b-5p by miRNA sponges improved IL-23-mediated expansion of Vγ2Vδ2 T cells and restored the ability of these cells to produce anti-tuberculosis cytokines. These results support our hypothesis that tuberculosis can selectively impair a cytokine effect while sparing another and can induce exhaustion of T cells in response to the respective cytokine.
authors: Unit of Antituberculosis Immunity, CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences.
authors: Hongbo
authors: H
authors: Shen
authors: Clinic and Research Center of Tuberculosis, Shanghai Key Lab of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine.
authors: Jin
authors: J
authors: Gu
authors: Clinic and Research Center of Tuberculosis, Shanghai Key Lab of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine.
authors: Heping
authors: H
authors: Xiao
authors: Unit of Antituberculosis Immunity, CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences.
authors: Shanshan
authors: S
authors: Liang
authors: Unit of Antituberculosis Immunity, CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences.
authors: Enzhuo
authors: E
authors: Yang
authors: Unit of Antituberculosis Immunity, CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences.
authors: Rui
authors: R
authors: Yang
authors: Department of Microbiology and Immunology.|Center for Primate Biomedical Research, University of Illinois College of Medicine, Chicago.
authors: Dan
authors: D
authors: Huang
authors: Department of Microbiology and Immunology.|Center for Primate Biomedical Research, University of Illinois College of Medicine, Chicago.
authors: Crystal
authors: C
authors: Chen
authors: Department of Medical Microbiology and Parasitology, Shanghai Medical College, Fudan University, Shanghai, China.
authors: Feifei
authors: F
authors: Wang
authors: Department of Microbiology and Immunology.|Center for Primate Biomedical Research, University of Illinois College of Medicine, Chicago.
authors: Ling
authors: L
authors: Shen
authors: Department of Microbiology and Immunology.|Center for Primate Biomedical Research, University of Illinois College of Medicine, Chicago.|Institut Pasteur of Shanghai, China.
authors: Zheng W
authors: ZW
authors: Chen
mesh_terms: D000328:Adult; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D053759:Interleukin-23 / Q000037:antagonists & inhibitors* / Q000276:immunology; D055985:Latent Tuberculosis / Q000276:immunology*; D008297:Male; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D010755:Organophosphates / Q000276:immunology; D016692:Receptors, Antigen, T-Cell, gamma-delta; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology*
chemical_list: C467061:4-hydroxy-3-methyl-2-butenyl diphosphate; D007376:Interleukin-2; D053759:Interleukin-23; D010755:Organophosphates; D016692:Receptors, Antigen, T-Cell, gamma-delta; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human
keywords: JAK2/STAT3; T-cell exhaustion; Vγ2Vδ2 T cells; cytokine signaling; miRNA; tuberculosis