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Regulatory T Cells Depress Immune Responses to Protective Antigens in Active Tuberculosis

Jean-Michel Hougardy¹, Sammy Place¹, Marc Hildebrand², Annie Drowart³, Anne-Sophie Debrie^4,5, Camille Locht^4,5 and Franoise Mascart^1,6

¹ Laboratory of Vaccinology and Mucosal Immunity, Hôpital Erasme, Brussels, Belgium; ² Infectious Disease Department, Hôpital Saint-Pierre, Université Libre de Bruxelles, Brussels, Belgium; ³ Chest Department, Hôpital Brugmann, Université Libre de Bruxelles, Brussels, Belgium; ⁴ Institut Pasteur de Lille, Lille, France; ⁵ INSERM, U629, Lille, France; and ⁶ Immunobiology Clinic, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium

Correspondence and requests for reprints should be addressed to Professor Franoise Mascart, Hôpital Erasme, Immunobiology Clinic, 808 Route de Lennik, B-1070 Brussels, Belgium. E-mail: fmascart{at}ulb.ac.be

Rationale: Tuberculosis (TB) remains a leading cause of death, and the role of T-cell responses to control Mycobacterium tuberculosis infections is well recognized. Patients with latent TB infection develop strong IFN- responses to the protective antigen heparin-binding hemagglutinin (HBHA), whereas patients with active TB do not.

Objectives: We investigated the mechanism of this difference and evaluated the possible involvement of regulatory T (Treg) cells and/or cytokines in the low HBHA T-cell responses of patients with active TB.

Methods: The impact of anti–transforming growth factor (TGF)- and anti–IL-10 antibodies and of Treg cell depletion on the HBHA-induced IFN- secretion was analyzed, and the Treg cell phenotype was characterized by flow cytometry.

Measurements and Main Results: Although the addition of anti–TGF- or anti–IL-10 antibodies had no effect on the HBHA-induced IFN- secretion in patients with active TB, depletion of CD4⁺CD25^highFOXP3⁺ T lymphocytes resulted in the induction by HBHA of IFN- concentrations that reached levels similar to those obtained for latent TB infection. No effect was noted on the early-secreted antigen target–6 or candidin T-cell responses.

Conclusions: Specific CD4⁺CD25^highFOXP3⁺ T cells depress the T-cell–mediated immune responses to the protective mycobacterial antigen HBHA during active TB in humans.

Key Words: tuberculosis • regulatory T cells • heparin-binding hemagglutinin

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Elevated levels of regulatory T cells with the CD4+CD25+FOXP3+ phenotype have been detected in patients with tuberculosis. What This Study Adds to the Field We show that regulatory T cells suppress IFN- responses preferably to protective antigens, such as the novel heparin-binding hemagglutinin, suggesting that the induction of these cells constitutes an important escape mechanism of Mycobacterium tuberculosis.

 

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