Molecular Recognition of Lipid Antigens by T Cell Receptors

doi:10.1084/jem.189.1.195

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J. Exp. Med., Volume 189, Number 1, January 4, 1999 195-205

Molecular Recognition of Lipid Antigens by T Cell Receptors

By Ethan P. Grant,^* Massimo Degano, Jean-Pierre Rosat,^* Steffen Stenger,^§ Robert L. Modlin,^§ Ian A. Wilson, Steven A. Porcelli,^* and Michael B. Brenner^*

From the ^* Lymphocyte Biology Section, Division of Rheumatology, Immunology, and Allergy, Department of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115; the Department of Molecular Biology and Skaggs Institute of Chemical Biology, Scripps Research Institute, La Jolla, California 92037; and the ^§ Division of Dermatology, University of California Los Angeles School of Medicine, Los Angeles, California 90095

The T cell antigen receptor (TCR) mediates recognition of peptide antigens bound in the groove of major histocompatibilitycomplex (MHC) molecules. This dual recognition is mediated bythe complementarity-determining residue (CDR) loops of the $alpha$ and $beta$ chains of a single TCR which contact exposed residues of thepeptide antigen and amino acids along the MHC $alpha$ helices. The recentdescription of T cells that recognize hydrophobic microbial lipidantigens has challenged immunologists to explain, in molecularterms, the nature of this interaction. Structural studies on themurine CD1d1 molecule revealed an electrostatically neutral putativeantigen-binding groove beneath the CD1 $alpha$ helices. Here, we demonstratethat $alpha$ / $beta$ TCRs, when transferred into TCR-deficient recipient cells,confer specificity for both the foreign lipid antigen and CD1isoform. Sequence analysis of a panel of CD1-restricted, lipid-specificTCRs reveals the incorporation of template-independent N nucleotidesthat encode diverse sequences and frequent charged basic residuesat the V(D)J junctions. These sequences permit a model for recognitionin which the TCR CDR3 loops containing charged residues projectbetween the CD1 $alpha$ helices, contacting the lipid antigen hydrophilichead moieties as well as adjacent CD1 residues in a manner thatexplains antigen specificity and CD1 restriction.

Key words: CD1; antigen presentation; T cell receptor; Mycobacterium tuberculosis; mycolic acid

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