title: Human leukocyte antigens A*3001 and A*3002 show distinct peptide-binding patterns of the Mycobacterium tuberculosis protein TB10.4: consequences for immune recognition.
abstract: High-tuberculosis (TB)-burden countries are located in sub-Saharan Africa. We examined the frequency of human leukocyte antigen (HLA) alleles, followed by recombinant expression of the most frequent HLA-A alleles, i.e., HLA-A*3001 and HLA-A*3002, to study differences in mycobacterial peptide presentation and CD8(+) T-cell recognition. We screened a peptide library (9-mer peptides with an 8-amino-acid overlap) for binding, affinity, and off-rate of the Mycobacterium tuberculosis-associated antigen TB10.4 and identified only three TB10.4 peptides with considerable binding to HLA-A*3001. In contrast, 22 peptides bound to HLA-A*3002. This reflects a marked difference in the binding preference between the two alleles, with A*3002 tolerating a more promiscuous peptide-binding pattern and A*3001 accommodating only a very selective peptide repertoire. Subsequent analysis of the affinity and off-rate of the binding peptides revealed a strong affinity (8 nM to 7 μM) and moderate off-rate (20 min to 3 h) for both alleles. Construction of HLA-A*3001 and HLA-A*3002 tetramers containing selected binding peptides from TB10.4, including a peptide which was shared among both alleles, QIMYNYPAM (TB10.4(3-11)), allowed us to enumerate epitope-specific T cells in HLA-A*3001- and HLA-A*3002-typed patients with active TB. HLA-A*3001 and HLA-A*3002 major histocompatibility complex-peptide complexes were recognized in individuals with active TB, irrespective of their homozygous HLA-A*3001 or HLA-A*3002 genetic background. The antigen-specific T cells exhibited the CD45RA(+) CCR7(+) precursor phenotype and the interleukin-7 receptor (CD127), which were different from the phenotype and receptor exhibited by the parental CD8(+) T-cell population.
authors.affiliation: Department of Microbiology and Tumor Cell Biology, Karolinska Institutet, Nobels Väg 18, Stockholm SE-171 82, Sweden.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Axelsson-Robertson
authors.forename: Raija K
authors.initials: RK
authors.lastname: Ahmed
authors.forename: Frank F
authors.initials: FF
authors.lastname: Weichold
authors.forename: Marthie M
authors.initials: MM
authors.lastname: Ehlers
authors.forename: Marleen M
authors.initials: MM
authors.lastname: Kock
authors.forename: Donata
authors.initials: D
authors.lastname: Sizemore
authors.forename: Jerry
authors.initials: J
authors.lastname: Sadoff
authors.forename: Markus
authors.initials: M
authors.lastname: Maeurer
mesh_terms: D000595:Amino Acid Sequence; D000942:Antigens, Bacterial / Q000737:chemistry* / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D001665:Binding Sites; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D000939:Epitopes / Q000235:genetics / Q000276:immunology; D006680:HLA Antigens / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015234:HLA-A Antigens / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D009169:Mycobacterium tuberculosis; D019151:Peptide Library; D010455:Peptides / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D011485:Protein Binding; D013019:South Africa; D014397:Tuberculosis, Pulmonary / Q000276:immunology
chemical_list: D000942:Antigens, Bacterial; D000939:Epitopes; D006680:HLA Antigens; D015234:HLA-A Antigens; C541139:HLA-A*30:01 antigen; D019151:Peptide Library; D010455:Peptides; C501710:TB10.4 antigen, Mycobacterium tuberculosis