title: Extensive major histocompatibility complex class I binding promiscuity for Mycobacterium tuberculosis TB10.4 peptides and immune dominance of human leucocyte antigen (HLA)-B*0702 and HLA-B*0801 alleles in TB10.4 CD8 T-cell responses.
abstract: The molecular definition of major histocompatibility complex (MHC) class I-presented CD8(+) T-cell epitopes from clinically relevant Mycobacterium tuberculosis (Mtb) target proteins will aid in the rational design of T-cell-based diagnostics of tuberculosis (TB) and the measurement of TB vaccine-take. We used an epitope discovery system, based on recombinant MHC class I molecules that cover the most frequent Caucasian alleles [human leucocyte antigen (HLA)-A*0101, A*0201, A*0301, A*1101, A*2402, B*0702, B*0801 and B*1501], to identify MHC class I-binding peptides from overlapping 9-mer peptides representing the Mtb protein TB10.4. A total of 33 MHC class I-binding epitopes were identified, spread across the entire amino acid sequence, with some clustering at the N- and C-termini of the protein. Binding of individual peptides or closely related peptide species to different MHC class I alleles was frequently observed. For instance, the common motif of xIMYNYPAMx bound to six of eight alleles. Affinity (50% effective dose) and off-rate (half life) analysis of candidate Mtb peptides will help to define the conditions for CD8(+) T-cell interaction with their nominal MHC class I-peptide ligands. Subsequent construction of tetramers allowed us to confirm the recognition of some of the epitopes by CD8(+) T cells from patients with active pulmonary TB. HLA-B alleles served as the dominant MHC class I restricting molecules for anti-Mtb TB10.4-specific CD8(+) T-cell responses measured in CD8(+) T cells from patients with pulmonary TB.
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Axelsson-Robertson
authors.forename: Frank
authors.initials: F
authors.lastname: Weichold
authors.forename: Donata
authors.initials: D
authors.lastname: Sizemore
authors.forename: Markus
authors.initials: M
authors.lastname: Wulf
authors.forename: Yasir A W
authors.initials: YA
authors.lastname: Skeiky
authors.forename: Jerry
authors.initials: J
authors.lastname: Sadoff
authors.forename: Markus J
authors.initials: MJ
authors.lastname: Maeurer
mesh_terms: D000483:Alleles; D001665:Binding Sites; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D015235:HLA-B Antigens / Q000276:immunology*; D015793:HLA-B7 Antigen; D015795:HLA-B8 Antigen; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D010455:Peptides / Q000276:immunology*; D014397:Tuberculosis, Pulmonary / Q000175:diagnosis / Q000276:immunology
chemical_list: D015235:HLA-B Antigens; C477444:HLA-B*07:02 antigen; C509422:HLA-B*08:01 antigen; D015793:HLA-B7 Antigen; D015795:HLA-B8 Antigen; D015395:Histocompatibility Antigens Class I; D010455:Peptides