Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 210, Issue 4, Pages 729-741Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20120624
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Funding
- Burroughs Wellcome Fund for Translational Research
- National Institute of Allergy and Infectious Diseases (NIAID) [R01 AI04393, R01 AR 048632]
- NIAID [K08 AI089858]
- National Institutes of Health (NIH) [RO1 AI45889]
- NIH [AI26170, CFAR AI-051519]
- NIAID MHC Tetramer Facility [N01-AI25456]
- Medical Research Council [G0600105, MR/K00042X/1] Funding Source: researchfish
- MRC [MR/K00042X/1, G0600105] Funding Source: UKRI
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CD1c is expressed with high density on human dendritic cells (DCs) and B cells, yet its antigen presentation functions are the least well understood among CD1 family members. Using a CD1c-reactive T cell line (DN6) to complete an organism-wide survey of M. tuberculosis lipids, we identified C32 phosphomycoketide (PM) as a previously unknown molecule and a CD1c-presented antigen. CD1c binding and presentation of mycoketide antigens absolutely required the unusual, mycobacteria-specific lipid branching patterns introduced by polyketide synthase 12 (pks12). Unexpectedly, one TCR responded to diversely glycosylated and unglycosylated forms of mycoketide when presented by DCs and B cells. Yet cell-free systems showed that recognition was mediated only by the deglycosylated phosphoantigen. These studies identify antigen processing of a natural bacterial antigen in the human CD1c system, indicating that cells act on glycolipids to generate a highly simplified neoepitope composed of a sugar-free phosphate anion. Using knowledge of this processed antigen, we generated human CD1c tetramers, and demonstrate that CD1c-PM complexes stain T cell receptors (TCRs), providing direct evidence for a ternary interaction among CD1c-lipid-TCR. Furthermore, PM-loaded CD1c tetramers detect fresh human T cells from peripheral blood, demonstrating a polyclonal response to PM antigens in humans ex vivo.
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