title: Crystal structure of a complete ternary complex of T-cell receptor, peptide-MHC, and CD4.
abstract: Adaptive immunity depends on specific recognition by a T-cell receptor (TCR) of an antigenic peptide bound to a major histocompatibility complex (pMHC) molecule on an antigen-presenting cell (APC). In addition, T-cell activation generally requires binding of this same pMHC to a CD4 or CD8 coreceptor. Here, we report the structure of a complete TCR-pMHC-CD4 ternary complex involving a human autoimmune TCR, a myelin-derived self-peptide bound to HLA-DR4, and CD4. The complex resembles a pointed arch in which TCR and CD4 are each tilted ∼65° relative to the T-cell membrane. By precluding direct contacts between TCR and CD4, the structure explains how TCR and CD4 on the T cell can simultaneously, yet independently, engage the same pMHC on the APC. The structure, in conjunction with previous mutagenesis data, places TCR-associated CD3εγ and CD3εδ subunits, which transmit activation signals to the T cell, inside the TCR-pMHC-CD4 arch, facing CD4. By establishing anchor points for TCR and CD4 on the T-cell membrane, the complex provides a basis for understanding how the CD4 coreceptor focuses TCR on MHC to guide TCR docking on pMHC during thymic T-cell selection.
authors.affiliation: W. M. Keck Laboratory for Structural Biology, Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, MD 20850, USA.
authors.forename: Yiyuan
authors.initials: Y
authors.lastname: Yin
authors.forename: Xin Xiang
authors.initials: XX
authors.lastname: Wang
authors.forename: Roy A
authors.initials: RA
authors.lastname: Mariuzza
mesh_terms: D015704:CD4 Antigens / Q000737:chemistry*; D018360:Crystallography, X-Ray; D006801:Humans; D008285:Major Histocompatibility Complex; D008958:Models, Molecular; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry*; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry*
chemical_list: D015704:CD4 Antigens; D010455:Peptides; D011948:Receptors, Antigen, T-Cell