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-Chain Connecting Peptide Motif Promotes Close Approximation of the CD8 Coreceptor Allowing Efficient Signal Initiation1
* Laboratory of Transplantation Immunology and Nephrology, Department of Biomedicine, University Hospital Basel, Basel, Switzerland;
Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, Epalinges, Switzerland; and
Department of Immunology, Scripps Research Institute, La Jolla, CA 92037
The CD8 coreceptor contributes to the recognition of peptide-MHC (pMHC) ligands by stabilizing the TCR-pMHC interaction and enabling efficient signaling initiation. It is unclear though, which structural elements of the TCR ensure a productive association of the coreceptor. The 
-chain connecting peptide motif (-CPM) is a highly conserved sequence of eight amino acids in the membrane proximal region of the TCR -chain. TCRs lacking the -CPM respond poorly to low-affinity pMHC ligands and are unable to induce positive thymic selection. In this study we show that CD8 participation in ligand binding is compromised in T lineage cells expressing mutant -CPM TCRs, leading to a slight reduction in apparent affinity; however, this by itself does not explain the thymic selection defect. By fluorescence resonance energy transfer microscopy, we found that TCR-CD8 association was compromised for TCRs lacking the -CPM. Although high-affinity (negative-selecting) pMHC ligands showed reduced TCR-CD8 interaction, low-affinity (positive-selecting) ligands completely failed to induce molecular approximation of the TCR and its coreceptor. Therefore, the -CPM of a TCR is an important element in mediating CD8 approximation and signal initiation.
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 work was supported by grants from the Swiss National Science Foundation, European Association of Plastic Surgeons, Novartis, and Hoffmann La Roche (to E.P.), National Institutes of Health Grant R01AI074074 (to N.R.J.G.), and U.S. Cancer Research Institute (to M.A.D.), and T32HL07195-30 (to P.P.Y.).
2 Current address: Department of Molecular Microbiology and Immunology, University of Missouri, One Hospital Drive, Columbia, MO 65212.
3 Address correspondence and reprint requests to Dr. Ed Palmer, Laboratory of Transplantation Immunology and Nephrology, Department of Biomedicine, University Hospital Basel, Hebelstrasse 20, 4031 Basel, Switzerland. E-mail address: ed.palmer{at}unibas.ch
4 Abbreviations used in this paper: pMHC, peptide-MHC; ABA, azidobenzoic acid; -CPM, -chain connecting peptide motif; β2m, β2-microglobulin; CFP, cyan fluorescent protein; DP, CD4+CD8+ double positive; FRET, fluorescence resonance energy transfer; FTOC, fetal thymic organ culture; MFI, mean fluorescence intensity; SP, CD4–CD8+ single positive; TM, transmembrane; YFP, yellow fluorescent protein; wt, wild type.
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  R. Wang, K. Natarajan, and D. H. Margulies Structural Basis of the CD8{alpha}{beta}/MHC Class I Interaction: Focused Recognition Orients CD8{beta} to a T Cell Proximal Position J. Immunol., August 15, 2009; 183(4): 2554 - 2564. [Abstract] [Full Text] [PDF]
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