Selective Destruction of Interleukin 23–Induced Expansion of a Major Antigen–Specific γδ T-Cell Subset in Patients With Tuberculosis

• Published in: The Journal of infectious diseases Vol. 215; no. 3; pp. 420 - 430
• Main Authors: Shen, Hongbo, Gu, Jin, Xiao, Heping, Liang, Shanshan, Yang, Enzhuo, Yang, Rui, Huang, Dan, Chen, Crystal, Wang, Feifei, Shen, Ling, Chen, Zheng W.
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.02.2017
• Subjects: Adult; Cell Proliferation; Female; Humans; Interleukin-2 - antagonists & inhibitors; Interleukin-2 - metabolism; Interleukin-23 - antagonists & inhibitors; Interleukin-23 - immunology; Latent Tuberculosis - immunology; Major; Male; Mycobacterium tuberculosis - immunology; Organophosphates - immunology; PATHOGENESIS AND HOST RESPONSE; Receptors, Antigen, T-Cell, gamma-delta; Signal Transduction; STAT3 Transcription Factor - metabolism; T-Lymphocyte Subsets - immunology; Vγ2Vδ2 T cells; cytokine signaling; JAK2/STAT3; miRNA; T-cell exhaustion; tuberculosis
• ISSN: 0022-1899; 1537-6613; 1537-6613
• DOI: 10.1093/infdis/jiw511

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.