Extensive major histocompatibility complex class I binding promiscuity for Mycobacterium tuberculosis TB10.4 peptides and immune dominance of human leucocyte antigen (HLA)-B0702 and HLA-B0801 alleles in TB10.4 CD8⁺ T-cell responses

• Published in: Immunology Vol. 129; no. 4; pp. 496 - 505
• Main Authors: Axelsson-Robertson, Rebecca, Weichold, Frank, Sizemore, Donata, Wulf, Markus, Skeiky, Yasir A.W, Sadoff, Jerry, Maeurer, Markus J
• Format: Journal Article
• Language: English
• Published: Oxford, UK Oxford, UK : Blackwell Publishing Ltd 01.04.2010; Blackwell Publishing Ltd; Wiley Subscription Services, Inc; Blackwell Science Inc
• Subjects: Alleles; Amino acids; Autoimmune diseases; Binding Sites; CD8+ T cells; CD8-Positive T-Lymphocytes - immunology; CD8⁺ T cells; epitopes; Histocompatibility Antigens Class I - immunology; HLA-B Antigens - immunology; HLA-B7 Antigen; HLA-B8 Antigen; Humans; immune dominance; Mycobacterium tuberculosis; Mycobacterium tuberculosis - immunology; Original; Peptides; Peptides - immunology; TB10.4; Tuberculosis; Tuberculosis, Pulmonary - diagnosis; Tuberculosis, Pulmonary - immunology
• ISSN: 0019-2805; 1365-2567; 1365-2567
• DOI: 10.1111/j.1365-2567.2009.03201.x

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.