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Molecular basis of mycobacterial lipid antigen presentation by CD1c and its
recognition by ?? T cells
#MMPMID25298532
Roy S
; Ly D
; Li NS
; Altman JD
; Piccirilli JA
; Moody DB
; Adams EJ
Proc Natl Acad Sci U S A
2014[Oct]; 111
(43
): E4648-57
PMID25298532
show ga
CD1c is a member of the group 1 CD1 family of proteins that are specialized for
lipid antigen presentation. Despite high cell surface expression of CD1c on key
antigen-presenting cells and the discovery of its mycobacterial lipid antigen
presentation capability, the molecular basis of CD1c recognition by T cells is
unknown. Here we present a comprehensive functional and molecular analysis of ??
T-cell receptor (TCR) recognition of CD1c presenting mycobacterial
phosphomycoketide antigens. Our structure of CD1c with the mycobacterial
phosphomycoketide (PM) shows similarities to that of
CD1c-mannosyl-?1-phosphomycoketide in that the A' pocket accommodates the
mycoketide alkyl chain; however, the phosphate head-group of PM is shifted ?6 Å
in relation to that of mannosyl-?1-PM. We also demonstrate a bona fide
interaction between six human TCRs and CD1c-mycoketide complexes, measuring high
to moderate affinities. The crystal structure of the DN6 TCR and mutagenic
studies reveal a requirement of five complementarity determining region (CDR)
loops for CD1c recognition. Furthermore, mutagenesis of CD1c reveals residues in
both the ?1 and ?2 helices involved in TCR recognition, yet not entirely
overlapping among the examined TCRs. Unlike patterns for MHC I, no archetypical
binding footprint is predicted to be shared by CD1c-reactive TCRs, even when
recognizing the same or similar antigens.
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