A Diverse Lipid Antigen-Specific TCR Repertoire Is Clonally Expanded during Active Tuberculosis.
William S DeWittKrystle K Q YuDamien Beau WilburnAnna SherwoodMarissa VignaliCheryl L DayThomas J ScribaHarlan S RobinsWillie J SwansonRyan O EmersonPhilip H BradleyChetan SeshadriPublished in: Journal of immunology (Baltimore, Md. : 1950) (2018)
Human T cells that recognize lipid Ags presented by highly conserved CD1 proteins often express semi-invariant TCRs, but the true diversity of lipid Ag-specific TCRs remains unknown. We use CD1b tetramers and high-throughput immunosequencing to analyze thousands of TCRs from ex vivo-sorted or in vitro-expanded T cells specific for the mycobacterial lipid Ag, glucose monomycolate. Our results reveal a surprisingly diverse repertoire resulting from editing of germline-encoded gene rearrangements analogous to MHC-restricted TCRs. We used a distance-based metric (TCRDist) to show how this diverse TCR repertoire builds upon previously reported conserved motifs by including subject-specific TCRs. In a South African cohort, we show that TCRDist can identify clonal expansion of diverse glucose monomycolate-specific TCRs and accurately distinguish patients with active tuberculosis from control subjects. These data suggest that similar mechanisms govern the selection and expansion of peptide and lipid Ag-specific T cells despite the nonpolymorphic nature of CD1.
Keyphrases
- mycobacterium tuberculosis
- high throughput
- fatty acid
- quantum dots
- machine learning
- transcription factor
- crispr cas
- gene expression
- genome wide
- emergency department
- highly efficient
- single cell
- oxidative stress
- immune response
- adipose tissue
- dna repair
- data analysis
- artificial intelligence
- dendritic cells
- electronic health record
- adverse drug
- pluripotent stem cells
- induced pluripotent stem cells