The T cell antigen receptor (TCR) mediates recognition of peptide antigens
bound ill the groove of major histocompatibility complex (MHC) molecules. T
his dual recognition is mediated by the complementarity-determining residue
(CDR) loops of the alpha and beta chains of a single TCR which contact exp
osed residues of the peptide antigen and amino acids along the MHC alpha he
lices. Thr recent description of T cells that recognize hydrophobic microbi
al lipid antigens has challenged immunologists to explain, ill molecular te
rms, the nature of this interaction. Structural studies on the murine CD1d1
molecule revealed an electrostatically neutral putative antigen-binding gr
oove beneath the CD1 alpha helices. Here, we demonstrate that alpha/beta TC
Rs, when transferred into TCR-deficient recipient cells, confer specificity
for both the foreign lipid antigen and CD1 isoform. Sequence analysis of a
panel of CD1-restricted, lipid-specific TCRs reveals the incorporation of
template-independent N nucleotides that encode diverse sequences and freque
nt charged basic residues at the V(D)J junctions. These sequences permit a
model for recognition in which the TCR CDR3 loops containing charged residu
es project between the CD1 alpha helices, contacting the lipid antigen hydr
ophilic head moieties as well as adjacent CD1 residues ill a manner that ex
plains antigen specificity and CD1 restriction.