title: Hypoxia induces an immunodominant target of tuberculosis specific T cells absent from common BCG vaccines.
abstract: M. tuberculosis (MTB) species-specific antigenic determinants of the human T cell response are important for immunodiagnosis and vaccination. As hypoxia is a stimulus in chronic tuberculosis infection, we analyzed transcriptional profiles of MTB subject to 168 hours of hypoxia to test the hypothesis that upregulation by hypoxia might result in gene products being recognized as antigens. We identified upregulation of two region of difference (RD) 11 (Rv2658C and Rv2659c), and one RD2 (Rv1986) absent from commonly used BCG strains. In MTB infected persons, the IL-2 ELISpot response to Rv1986 peptides was several times greater than the corresponding IFN-γ response to the reference immunodominant ESAT-6 or CFP-10 antigens. The IL-2 response was confined to two epitopic regions containing residues 61-80 and 161-180. The biggest population of IL-2 secreting T cells was single cytokine positive central memory T cells. The IL-2 response to live MTB bacilli lacking Rv1986 was significantly lower than the response to wild type or mutant complemented with Rv1986. In addition, the IL-2 response to Rv1986 was significantly lower in HIV-TB co-infected persons than in HIV uninfected persons, and significantly increased during antiretroviral therapy. These findings demonstrate that Rv1986 is an immunodominant target of memory T cells and is therefore of relevance when considering the partial efficacy of currently used BCG vaccines and provide evidence for a clinical trial comparing BCG strains.
authors.affiliation: Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Observatory, South Africa.
authors.forename: Hannah Priyadarshini
authors.initials: HP
authors.lastname: Gideon
authors.forename: Katalin Andrea
authors.initials: KA
authors.lastname: Wilkinson
authors.forename: Tige R
authors.initials: TR
authors.lastname: Rustad
authors.forename: Tolu
authors.initials: T
authors.lastname: Oni
authors.forename: Heinner
authors.initials: H
authors.lastname: Guio
authors.forename: Robert Andrew
authors.initials: RA
authors.lastname: Kozak
authors.forename: David R
authors.initials: DR
authors.lastname: Sherman
authors.forename: Graeme
authors.initials: G
authors.lastname: Meintjes
authors.forename: Marcel A
authors.initials: MA
authors.lastname: Behr
authors.forename: Hans Martin
authors.initials: HM
authors.lastname: Vordermeier
authors.forename: Douglas Brownlee
authors.initials: DB
authors.lastname: Young
authors.forename: Robert John
authors.initials: RJ
authors.lastname: Wilkinson
mesh_terms: D000942:Antigens, Bacterial / Q000235:genetics / Q000276:immunology; D001500:BCG Vaccine / Q000276:immunology; D020869:Gene Expression Profiling; D006801:Humans; D000860:Hypoxia / Q000276:immunology*; D016056:Immunodominant Epitopes / Q000096:biosynthesis / Q000235:genetics*; D007156:Immunologic Memory; D037182:T-Cell Antigen Receptor Specificity; D013601:T-Lymphocytes / Q000276:immunology*; D015533:Transcriptional Activation; D014376:Tuberculosis / Q000276:immunology*
chemical_list: D000942:Antigens, Bacterial; D001500:BCG Vaccine; D016056:Immunodominant Epitopes