STAT3 expression by myeloid cells is detrimental for the T- cell-mediated control of infection with Mycobacterium tuberculosis

PLoS Pathog. 2018 Jan 16;14(1):e1006809. doi: 10.1371/journal.ppat.1006809. eCollection 2018 Jan.

Abstract

STAT3 is a master regulator of the immune responses. Here we show that M. tuberculosis-infected stat3fl/fl lysm cre mice, defective for STAT3 in myeloid cells, contained lower bacterial load in lungs and spleens, reduced granuloma extension but higher levels of pulmonary neutrophils. STAT3-deficient macrophages showed no improved control of intracellular mycobacterial growth. Instead, protection associated to elevated ability of stat3fl/fl lysm cre antigen-presenting cells (APCs) to release IL-6 and IL-23 and to stimulate IL-17 secretion by mycobacteria-specific T cells. The increased IL-17 secretion accounted for the improved control of infection since neutralization of IL-17 receptor A in stat3fl/fl lysm cre mice hampered bacterial control. APCs lacking SOCS3, which inhibits STAT3 activation via several cytokine receptors, were poor inducers of priming and of the IL-17 production by mycobacteria-specific T cells. In agreement, socs3fl/fl cd11c cre mice deficient of SOCS3 in DCs showed increased susceptibility to M. tuberculosis infection. While STAT3 in APCs hampered IL-17 responses, STAT3 in mycobacteria-specific T cells was critical for IL-17 secretion, while SOCS3 in T cells impeded IL-17 secretion. Altogether, STAT3 signalling in myeloid cells is deleterious in the control of infection with M. tuberculosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Macrophages / immunology
  • Macrophages / metabolism
  • Mice
  • Mice, Transgenic
  • Mycobacterium tuberculosis / immunology*
  • Myeloid Cells / metabolism*
  • STAT3 Transcription Factor / genetics*
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction / genetics
  • T-Lymphocytes / immunology*
  • Tuberculosis / genetics
  • Tuberculosis / immunology*
  • Tuberculosis / metabolism

Substances

  • STAT3 Transcription Factor

Grant support

This study was supported by the Swedish Research Council grant VR/2016-19/2015-02296 (www.vr.se/inenglish), The Swedish Foundation for International Cooperation in Research and Higher Education (www.stint.se/en), The Swedish Heart and Lung Foundation 2015-17/20140641 (www.hjart-lungfonden.se), the Chinese Scholarship Council (www.en.csc.edu.cn/) and the Karolinska Institutet (www.ki.se). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.