HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0901276v1 183/4/2554    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Wang, R. Articles by Margulies, D. H. PubMed PubMed Citation Articles by Wang, R. Articles by Margulies, D. H.

Structural Basis of the CD8β/MHC Class I Interaction: Focused Recognition Orients CD8β to a T Cell Proximal Position^1,2

Molecular Biology Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892

In the immune system, B cells, dendritic cells, NK cells, and T lymphocytes all respond to signals received via ligand binding to receptors and coreceptors. Although the specificity of T cell recognition is determined by the interaction of T cell receptors with MHC/peptide complexes, the development of T cells in the thymus and their sensitivity to Ag are also dependent on coreceptor molecules CD8 (for MHC class I (MHCI)) and CD4 (for MHCII). The CD8β heterodimer is a potent coreceptor for T cell activation, but efforts to understand its function fully have been hampered by ignorance of the structural details of its interactions with MHCI. In this study we describe the structure of CD8β in complex with the murine MHCI molecule H-2D^d at 2.6 Å resolution. The focus of the CD8β interaction is the acidic loop (residues 222–228) of the 3 domain of H-2D^d. The β subunit occupies a T cell membrane proximal position, defining the relative positions of the CD8 and CD8β subunits. Unlike the CD8 homodimer, CD8β does not contact the MHCI ₂- or β₂-microglobulin domains. Movements of the CD8 CDR2 and CD8β CDR1 and CDR2 loops as well as the flexibility of the H-2D^d CD loop facilitate the monovalent interaction. The structure resolves inconclusive data on the topology of the CD8β/MHCI interaction, indicates that CD8β is crucial in orienting the CD8β heterodimer, provides a framework for understanding the mechanistic role of CD8β in lymphoid cell signaling, and offers a tangible context for design of structurally altered coreceptors for tumor and viral immunotherapy.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This research was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health.

² The sequences presented in this article have been submitted to GenBank under accession numbers GQ247790 and GQ247791.

³ Address correspondence and reprint requests to Dr. Kannan Natarajan, or Dr. David H. Margulies, Molecular Biology Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 10, Room 11N311, 10 Center Drive, Bethesda, MD 20892-1892. E-mail addresses: knatarajan{at}niaid.nih.gov and dhm{at}nih.gov

⁴ Abbreviations used in this paper: MHCI, MHC class I molecule; β₂m, β₂-microglobulin; mβ₂m, murine β₂m; TL, thymic leukemia.

⁵ The online version of this article contains supplemental material.