Molecular recognition of lipid antigens by T cell receptors

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.