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Identification of CD1b-restricted human T cells recognizing a mycobacterial adjuvant, trehalose monomycolate (TMM)

ABSTRACT: Mycobacterium tuberculosis causes tuberculosis (TB) which remains one of the world’s deadliest diseases. As mycobacteria are protected by its thick lipid cell wall, the host has developed immune systems targeting their unique lipids. Among them is an unconventional T cell subset called mycolipid-specific T cells restricted by common antigen-presenting molecules, such as CD1. Here, we identified novel mycolipid-specific T cells using a method combining bulk T cell stimulation with crude lipids and single cell-TCR-RNA-sequencing-based clonotypic analysis. In human PBMCs, a CD4+ T cell clone with cytotoxic signature, Y-50, was proliferated in response to mycobacterial crude lipid extract. Activity-based purification of using reporter cells reconstituted with Y-50 TCR identified trehalose monomycolate (TMM) as an antigen. CD1b was necessary and sufficient for the presentation of TMM to be recognized by Y-50. Y-50 TCRab chains displayed characteristic features, such as positively-charged CDR3a and extra-long CDR3b. Mutagenesis and structural analysis of TCRab suggested that these unique CDR3 properties were required for the recognition of TMM presented by CD1b. CD1b tetramer loaded with TMM could detect T cells with similar characteristics to Y-50 in uninfected healthy donors, but their frequency was significantly higher in PBMCs from TB patients. In this study, we identified pre-set unconventional T cells specific for a mycobacterial adjuvant, TMM.

ORGANISM(S): Homo sapiens

PROVIDER: GSE260931 | GEO | 2025/02/14

REPOSITORIES: GEO

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Project description:Mycobacteria of the Mycobacterium tuberculosis complex (MTBC) greatly impact on human and animal health worldwide. Mycobacterial life cycle is complex and the mechanisms resulting in pathogen infection and survival in host cells are not fully understood. Eurasian wild boar (Sus scrofa) are natural reservoir hosts for MTBC and a model for mycobacterial infection and tuberculosis (TB). In the wild boar TB model, mycobacterial infection affects the expression of innate and adaptive immune response genes in mandibular lymph nodes and oropharyngeal tonsils and biomarkers have been proposed as correlates with resistance to natural infection. However, the mechanisms used by mycobacteria to manipulate host immune response are not fully characterized. Our hypothesis is that the immune system proteins under-represented in infected animals when compared to uninfected controls are used by mycobacteria to guarantee pathogen infection and transmission. To address this hypothesis, a comparative proteomics approach was used to compare host response between uninfected (TB-) and M. bovis-infected young (TB+) and adult animals with different infection status [TB lesions localized in the head (TB+) or affecting multiple organs (TB++)]. The results identified host immune system proteins that play an important role in host response to mycobacteria. Calcium binding protein A9, Heme peroxidase, Lactotransferrin, Cathelicidin and Peptidoglycan-recognition protein were under-represented in TB+ animals when compared to uninfected TB- controls but protein levels increased as infection progressed in TB++ animals when compared to TB- and/or TB+ adult wild boar. MHCI was the only protein over-represented in TB+ adult wild boar when compared to uninfected TB- controls. The results reported here suggested that M. bovis manipulates host immune response by reducing the production of immune system proteins. However, as infection progresses, wild boar immune response recover to limit pathogen multiplication and promote survival that also facilitates pathogen transmission.

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Identification of CD1b-restricted human T cells recognizing a mycobacterial adjuvant, trehalose monomycolate (TMM)

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