title: Antimicrobial activity of MHC class I-restricted CD8+ T cells in human tuberculosis.
abstract: Studies of mouse models of tuberculosis (TB) infection have indicated a central role for MHC class I-restricted CD8+ T cells in protective immunity. To define antigens and epitopes of Mycobacterium tuberculosis (MTB) proteins that are presented by infected cells to CD8+ T cells, we screened 40 MTB proteins for HLA class I A*0201-binding motifs. Peptides that bound with high affinity to purified HLA molecules were subsequently analyzed for recognition by CD8+ cytotoxic T lymphocytes. We identified three epitopes recognized by CD8+ T cells from patients recovering from TB infection. Those three epitopes were derived from three different antigens: thymidylate synthase (ThyA(30-38)), RNA polymerase beta-subunit (RpoB(127-135)), and a putative phosphate transport system permease protein A-1 (PstA1(75-83)). In addition, CD8+ T cell lines specific for three peptides (ThyA(30-38), PstA1(75-83), and 85B(15-23)) were generated from peripheral blood mononuclear cells of normal HLA-A*0201 donors. These CD8+ T cell lines specifically recognized MTB-infected macrophages, as demonstrated by production of IFN-gamma and lysis of the infected target cells. Finally, CD8+ cytotoxic T lymphocytes reduced the viability of the intracellular MTB, providing evidence that CD8+ T cell recognition of MHC class I-restricted epitopes of these MTB antigens can contribute to effective immunity against the pathogen.
authors.affiliation: Division of Dermatology, University of California School of Medicine, Los Angeles, CA 90095, USA.
authors.forename: S
authors.initials: S
authors.lastname: Cho
authors.forename: V
authors.initials: V
authors.lastname: Mehra
authors.forename: S
authors.initials: S
authors.lastname: Thoma-Uszynski
authors.forename: S
authors.initials: S
authors.lastname: Stenger
authors.forename: N
authors.initials: N
authors.lastname: Serbina
authors.forename: R J
authors.initials: RJ
authors.lastname: Mazzaccaro
authors.forename: J L
authors.initials: JL
authors.lastname: Flynn
authors.forename: P F
authors.initials: PF
authors.lastname: Barnes
authors.forename: S
authors.initials: S
authors.lastname: Southwood
authors.forename: E
authors.initials: E
authors.lastname: Celis
authors.forename: B R
authors.initials: BR
authors.lastname: Bloom
authors.forename: R L
authors.initials: RL
authors.lastname: Modlin
authors.forename: A
authors.initials: A
authors.lastname: Sette
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D014376:Tuberculosis / Q000276:immunology*
chemical_list: D015395:Histocompatibility Antigens Class I; D007371:Interferon-gamma