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Mycobacterial Lipopeptides Elicit CD4⁺ CTLs in Mycobacterium tuberculosis-Infected Humans¹

Max Bastian^*, Tobias Braun, Heiko Bruns^*, Martin Röllinghoff and Steffen Stenger^2,*

^* Institut für Medizinische Mikrobiologie und Hygiene, Universitätsklinik Ulm, Ulm, Germany; and Institut für Klinische Mikrobiologie, Immunologie und Hygiene, Friedrich-Alexander Universität, Erlangen-Nürnberg, Germany

In searching for immunogenic molecules with the potential to induce protective immune responses against tuberculosis, we developed an ex vivo model to study frequency, phenotype, and effector functions of human T lymphocytes recognizing hydrophobic Ags of Mycobacterium tuberculosis (M.Tb). To obtain unbiased results, we characterized T lymphocytes responding to a crude cell wall extract (chloroform methanol extract of M.Tb (M.Tb-CME)) containing a broad spectrum of mycobacterial glycolipids and lipopeptides. A significant proportion of T lymphocytes recognized M.Tb-CME (290 IFN-⁺ T cells/10⁵ PBMCs) and developed to effector memory cells as determined by the expression of CD45RO and the chemokine receptors CXCR3 and CCR5. Expanded lymphocytes fulfilled all criteria required for an efficient immune response against tuberculosis: 1) release of macrophage-activating Th1 cytokines and chemokines required for the spatial organization of local immune responses, 2) cytolytic activity against Ag-pulsed macrophages, and 3) recognition of infected macrophages and killing of the intracellular bacteria. Phenotypically, M.Tb-CME-expanded cells were CD4⁺ and MHC class II restricted, challenging current concepts that cytotoxic and antimicrobial effector cells are restricted to the CD8⁺ T cell subset. Pretreatment of M.Tb-CME with protease or chemical delipidation abrogated the biological activity, suggesting that responses were directed toward mycobacterial lipopeptides. These findings suggest that lipidated peptides are presented by M.Tb-infected macrophages and elicit CD4⁺ cytolytic and antimicrobial T lymphocytes. Our data support an emerging concept to include hydrophobic microbial Ags in vaccines against tuberculosis.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the German Research Foundation (SFB643), the European Union (VIth Framework, TB-VAC), and the Interdisciplinary Center for Clinical Research in Erlangen.

² Address correspondence and reprint requests to Dr. Steffen Stenger, Institut für Medizinische Mikrobiologie und Hygiene, Universitätsklinik Ulm, Robert Koch-Strasse 8, D-89081 Ulm, Germany. E-mail address: steffen.stenger{at}uniklinik-ulm.de

³ Abbreviations used in this paper: M.Tb, Mycobacterium tuberculosis; BCG, bacille Calmette Guérin; CM, complete medium; M.Tb-CME, chloroform methanol extract of M.Tb; PPD, purified protein derivative; ESAT6, early secretory antigenic target 6; DC, dendritic cell; MOI, multiplicity of infection.