Mannose-capped lipoarabinomannan- and prostaglandin E2-dependent expansion of regulatory T cells in human Mycobacterium tuberculosis infection

Ankita Garg, Peter F. Barnes, Sugata Roy, María F. Quiroga, Shiping Wu, Verónica E. García, Stephan R. Krutzik, Steven E. Weis, Ramakrishna Vankayalapati

Research output: Contribution to journalArticle

79 Scopus citations

Abstract

We evaluated the role of regulatory T cells (CD4+ CD25+ Foxp3+ cells, Tregs) in human Mycobacterium tuberculosis infection. Tregs were expanded in response to M. tuberculosis in healthy tuberculin reactors, but not in tuberculin-negative individuals. The M. tuberculosis mannose-capped lipoarabinomannan (ManLAM) resulted in regulatory T cell expansion, whereas the M. tuberculosis 19-kDa protein and heat shock protein 65 had no effect. Anti-IL-10 and anti-TGF-β alone or in combination, did not reduce expansion of Tregs. In contrast, the cyclooxygenase enzyme-2 inhibitor NS398 significantly inhibited expansion of Tregs, indicating that prostaglandin E2 (PGE2) contributes to Treg expansion. Monocytes produced PGE2 upon culturing with heat-killed M. tuberculosis or ManLAM, and T cells from healthy tuberculin reactors enhanced PGE2 production by monocytes. Expanded Tregs produced significant amounts of TGF-b and IL-10 and depletion of Tregs from PBMC of these individuals increased the frequency of M. tuberculosis-responsive CD4+ IFN-γ cells. Culturing M. tuberculosis-expanded Tregs with autologous CD8+ cells decreased the frequency of IFN-γ +cells. Freshly isolated PBMC from tuberculosis patients had increased percentages of Tregs, compared to healthy tuberculin reactors. These findings demonstrate that Tregs expand in response to M. tuberculosis through mechanisms that depend on ManLAM and PGE2.

Original languageEnglish
Pages (from-to)459-469
Number of pages11
JournalEuropean Journal of Immunology
Volume38
Issue number2
DOIs
StatePublished - Feb 2008

Keywords

  • Bacterial infection
  • Human
  • Tregs

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