title: Immunological consequences of intragenus conservation of Mycobacterium tuberculosis T-cell epitopes.
abstract: A previous unbiased genome-wide analysis of CD4 Mycobacterium tuberculosis (MTB) recognition using peripheral blood mononuclear cells from individuals with latent MTB infection (LTBI) or nonexposed healthy controls (HCs) revealed that certain MTB sequences were unexpectedly recognized by HCs. In the present study, it was found that, based on their pattern of reactivity, epitopes could be divided into LTBI-specific, mixed reactivity, and HC-specific categories. This pattern corresponded to sequence conservation in nontuberculous mycobacteria (NTMs), suggesting environmental exposure as an underlying cause of differential reactivity. LTBI-specific epitopes were found to be hyperconserved, as previously reported, whereas the opposite was true for NTM conserved epitopes, suggesting that intragenus conservation also influences host pathogen adaptation. The biological relevance of this observation was demonstrated further by several observations. First, the T cells elicited by MTB/NTM cross-reactive epitopes in HCs were found mainly in a CCR6(+)CXCR3(+) memory subset, similar to findings in LTBI individuals. Thus, both MTB and NTM appear to elicit a phenotypically similar T-cell response. Second, T cells reactive to MTB/NTM-conserved epitopes responded to naturally processed epitopes from MTB and NTMs, whereas T cells reactive to MTB-specific epitopes responded only to MTB. Third, cross-reactivity could be translated to antigen recognition. Several MTB candidate vaccine antigens were cross-reactive, but others were MTB-specific. Finally, NTM-specific epitopes that elicit T cells that recognize NTMs but not MTB were identified. These epitopes can be used to characterize T-cell responses to NTMs, eliminating the confounding factor of MTB cross-recognition and providing insights into vaccine design and evaluation.
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037; and cecilia@liai.org.
authors.forename: Cecilia S
authors.initials: CS
authors.lastname: Lindestam Arlehamn
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037; and.
authors.forename: Sinu
authors.initials: S
authors.lastname: Paul
authors.affiliation: Institute for Research in Biomedicine, Università della Svizzera Italiana, 6500 Bellinzona, Switzerland.
authors.forename: Federico
authors.initials: F
authors.lastname: Mele
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037; and.
authors.forename: Charlie
authors.initials: C
authors.lastname: Huang
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037; and.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Greenbaum
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037; and.
authors.forename: Randi
authors.initials: R
authors.lastname: Vita
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037; and.
authors.forename: John
authors.initials: J
authors.lastname: Sidney
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037; and.
authors.forename: Bjoern
authors.initials: B
authors.lastname: Peters
authors.affiliation: Institute for Research in Biomedicine, Università della Svizzera Italiana, 6500 Bellinzona, Switzerland.
authors.forename: Federica
authors.initials: F
authors.lastname: Sallusto
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037; and.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sette
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D000942:Antigens, Bacterial / Q000235:genetics* / Q000276:immunology*; D016022:Case-Control Studies; D017124:Conserved Sequence; D003429:Cross Reactions; D018984:Epitopes, T-Lymphocyte / Q000235:genetics* / Q000276:immunology*; D016680:Genome, Bacterial; D055106:Genome-Wide Association Study; D054884:Host-Pathogen Interactions / Q000235:genetics / Q000276:immunology; D006801:Humans; D055985:Latent Tuberculosis / Q000235:genetics / Q000276:immunology / Q000382:microbiology; D008969:Molecular Sequence Data; D009169:Mycobacterium tuberculosis / Q000235:genetics* / Q000276:immunology*; D009170:Nontuberculous Mycobacteria / Q000235:genetics / Q000276:immunology; D054399:Receptors, CCR6 / Q000378:metabolism; D054367:Receptors, CXCR3 / Q000378:metabolism; D013045:Species Specificity; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000382:microbiology; D032581:Tuberculosis Vaccines / Q000235:genetics / Q000276:immunology
chemical_list: D000942:Antigens, Bacterial; C106311:CCR6 protein, human; C515187:CXCR3 protein, human; D018984:Epitopes, T-Lymphocyte; D054399:Receptors, CCR6; D054367:Receptors, CXCR3; D032581:Tuberculosis Vaccines
keywords: NTM; T-cell epitope; T-cell subset; epitope conservation; tuberculosis