期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：2
页码：E147-E155
DOI：10.1073/pnas.1416537112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceMycobacterium tuberculosis (MTB) infection is one of the most common diseases worldwide. The Mycobacteria are a large bacterial family that includes MTB and nontuberculous mycobacteria commonly found in the environment (NTMs). We have shown that non-MTB-infected and non-bacillus Calmette-Guerin-vaccinated individuals nevertheless react to MTB-derived sequences. This reactivity can be explained by conservation of the epitope sequence in NTMs. Thus, the widespread exposure to various species of Mycobacteria influences reactivity to MTB and NTMs. We identified epitopes that are found only in NTMs, allowing dissociation of MTB- versus NTM-specific reactivity. These epitopes, in conjunction with epitopes specific to latent MTB infection, will provide a novel tool to study host-pathogen dynamics in the context of the design and evaluation of MTB vaccines and diagnostics. 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.
