IL-23-dependent IL-17 drives Th1-cell responses following Mycobacterium bovis BCG vaccination

Radha Gopal, Yinyao Lin, Nataša Obermajer, Samantha Slight, Nikhil Nuthalapati, Mushtaq Ahmed, Pawel Kalinski, Shabaana A. Khader

Research output: Contribution to journalArticlepeer-review

115 Scopus citations

Abstract

The generation of effective type 1 T helper (Th1)-cell responses is required for immunity against intracellular bacteria. However, some intracellular bacteria require interleukin (IL)-17 to drive Th1-cell immunity and subsequent protective host immunity. Here, in a model of Mycobacterium bovis Bacille Calmette-Guerin (BCG) vaccination in mice, we demonstrate that the dependence on IL-17 to drive Th1-cell responses is a host mechanism to overcome bacteria-induced IL-10 inhibitory effects. We show that BCG-induced prostaglandin-E2 (PGE2) promotes the production of IL-10 which limits Th1-cell responses, while simultaneously inducing IL-23 and Th17-cell differentiation. The ability of IL-17 to downregulate IL-10 and induce IL-12 production allows the generation of subsequent Th1-cell responses. Accordingly, BCG-induced Th17-cell responses precede the generation of Th1-cell responses in vivo, whereas the absence of the IL-23 pathway decreases BCG vaccine-induced Th17 and Th1-cell immunity and subsequent vaccine-induced protection upon M. tuberculosis challenge. Importantly, in the absence of IL-10, BCG-induced Th1-cell responses occur in an IL-17-independent manner. These novel data demonstrate a role for the IL-23/IL-17 pathway in driving Th1-cell responses, specifically to overcome IL-10-mediated inhibition and, furthermore, show that in the absence of IL-10, the generation of BCG-induced Th1-cell immunity is IL-17 independent.

Original languageEnglish
Pages (from-to)364-373
Number of pages10
JournalEuropean Journal of Immunology
Volume42
Issue number2
DOIs
StatePublished - Feb 2012

Keywords

  • Immune regulation
  • Immune responses
  • Intracellular bacteria
  • T helper cells

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