M. tuberculosis T Cell Epitope Analysis Reveals Paucity of Antigenic Variation and Identifies Rare Variable TB Antigens

• Published in: Cell host & microbe Vol. 18; no. 5; pp. 538 - 548
• Main Authors: Coscolla, Mireia, Copin, Richard, Sutherland, Jayne, Gehre, Florian, de Jong, Bouke, Owolabi, Olumuiya, Mbayo, Georgetta, Giardina, Federica, Ernst, Joel D., Gagneux, Sebastien
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11.11.2015
• Subjects: Antigenic Variation; Antigens, Bacterial - genetics; Antigens, Bacterial - immunology; Epitopes, T-Lymphocyte - genetics; Epitopes, T-Lymphocyte - immunology; Genetic Variation; Genome, Bacterial; Humans; Immune Evasion; Mycobacterium tuberculosis - classification; Mycobacterium tuberculosis - genetics; Mycobacterium tuberculosis - immunology; Phylogeny; Tuberculosis - immunology; Tuberculosis - microbiology
• ISSN: 1931-3128; 1934-6069; 1934-6069
• DOI: 10.1016/j.chom.2015.10.008

Pathogens that evade adaptive immunity typically exhibit antigenic variation. By contrast, it appears that although the chronic human tuberculosis (TB)-causing pathogen Mycobacterium tuberculosis needs to counter host T cell responses, its T cell epitopes are hyperconserved. Here we present an extensive analysis of the T cell epitopes of M. tuberculosis. We combined population genomics with experimental immunology to determine the number and identity of T cell epitope sequence variants in 216 phylogenetically diverse strains of M. tuberculosis. Antigen conservation is indeed a hallmark of M. tuberculosis. However, our analysis revealed a set of seven variable antigens that were immunogenic in subjects with active TB. These findings suggest that M. tuberculosis uses mechanisms other than antigenic variation to evade T cells. T cell epitopes that exhibit sequence variation may not be subject to the same evasion mechanisms, and hence vaccines that include such variable epitopes may be more efficacious. [Display omitted] •1,226 T cell epitopes sequenced from 216 diverse M. tuberculosis strains•Most known M. tuberculosis T cell epitopes are highly conserved•Comparative genomics identifies rare predicted epitopes with sequence variants•Immunogenicity of predicted epitopes and variants confirmed in human studies Pathogens that evade adaptive immunity typically exhibit antigenic variation. By contrast, Coscolla, Copin et al. find that T cell epitopes across diverse strains of M. tuberculosis are hyperconserved. They identify rare variant M. tuberculosis epitopes and confirm their immunogenicity in human studies. These findings have implications for TB vaccine design.