The T cell antigen receptor (TCR) mediates recognition of peptide antigens bound in the groove of major histocompatibility complex (MHC) molecules. This dual recognition is mediated by the complementarity-determining residue (CDR) loops of the α and β chains of a single TCR which contact exposed residues of the peptide antigen and amino acids along the MHC α helices. The recent description of T cells that recognize hydrophobic microbial lipid antigens has challenged immunologists to explain, in molecular terms, the nature of this interaction. Structural studies on the murine CD1d1 molecule revealed an electrostatically neutral putative antigen-binding groove beneath the CD1 α helices. Here, we demonstrate that α/β TCRs, 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 frequent charged basic residues at the V(D)J junctions. These sequences permit a model for recognition in which the TCR CDR3 loops containing charged residues project between the CD1 α helices, contacting the lipid antigen hydrophilic head moieties as well as adjacent CD1 residues in a manner that explains antigen specificity and CD1 restriction.
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4 January 1999
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January 04 1999
Molecular Recognition of Lipid Antigens by T Cell Receptors
Ethan P. Grant,
Ethan P. Grant
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
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Massimo Degano,
Massimo Degano
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
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Jean-Pierre Rosat,
Jean-Pierre Rosat
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
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Steffen Stenger,
Steffen Stenger
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
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Robert L. Modlin,
Robert L. Modlin
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
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Ian A. Wilson,
Ian A. Wilson
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
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Steven A. Porcelli,
Steven A. Porcelli
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
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Michael B. Brenner
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
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Ethan P. Grant
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
Massimo Degano
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
Jean-Pierre Rosat
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
Steffen Stenger
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
Robert L. Modlin
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
Ian A. Wilson
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
Steven A. Porcelli
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
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
Address correspondence to Michael B. Brenner, M.D., Brigham & Women's Hospital, Smith Bldg., Rm. 552, 75 Francis St., Boston, MA 02115. Phone: 617-525-1000; Fax: 617-525-1010; E-mail: [email protected]
Received:
October 13 1998
Online ISSN: 1540-9538
Print ISSN: 0022-1007
1999
J Exp Med (1999) 189 (1): 195–205.
Article history
Received:
October 13 1998
Citation
Ethan P. Grant, Massimo Degano, Jean-Pierre Rosat, Steffen Stenger, Robert L. Modlin, Ian A. Wilson, Steven A. Porcelli, Michael B. Brenner; Molecular Recognition of Lipid Antigens by T Cell Receptors . J Exp Med 4 January 1999; 189 (1): 195–205. doi: https://doi.org/10.1084/jem.189.1.195
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