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International Immunology Advance Access originally published online on November 1, 2007
International Immunology 2007 19(12):1413-1420; doi:10.1093/intimm/dxm111
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Published by Oxford University Press 2007.

Role of {alpha}3 domain of class I MHC molecules in the activation of high- and low-avidity CD8+ CTLs

Igor M. Belyakov1, Steven Kozlowski2, Michael Mage3, Jeffrey D. Ahlers1, Lisa F. Boyd3, David H. Margulies3 and Jay A. Berzofsky1

1 Molecular Immunogenetics and Vaccine Research Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
2 Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA
3 Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA

Correspondence to: I. M. Belyakov; E-mail: igorbelyakov{at}yahoo.com

CD8 can serve as a co-receptor or accessory molecule on the surface of CTL. As a co-receptor, CD8 can bind to the {alpha}3 domain of the same MHC class I molecules as the TCR to facilitate TCR signaling. To evaluate the role of the MHC class I molecule {alpha}3 domain in the activation of CD8+ CTL, we have produced a soluble 227 mutant of H-2Dd, with a point mutation in the {alpha}3 domain (Glu227->Lys). 227 mutant class I–peptide complexes were not able to effectively activate H-2Dd-restricted CD8 T cells in vitro, as measured by IFN-{gamma} production by an epitope-specific CD8+ CTL line. However, the 227 mutant class I–peptide complexes in the presence of another MHC class I molecule (H-2Kb) (that cannot present the peptide) with a normal {alpha}3 domain can induce the activation of CD8+ CTL. Therefore, in order to activate CD8+ CTL, the {alpha}3 domain of MHC class I does not have to be located on the same molecule with the {alpha}1 and {alpha}2 domains of MHC class I. A low-avidity CD8+ CTL line was significantly less sensitive to stimulation by the 227 mutant class I–peptide complexes in the presence of the H-2Kb molecule. Thus, low-avidity CTL may not be able to take advantage of the interaction between CD8 and the {alpha}3 domain of non-presenting class I MHC molecules, perhaps because of a shorter dwell time for the TCR–MHC interaction.

Keywords: cytotoxic T lymphocytes, MHC class I, avidity, epitope, peptide, TCR

Transmitting editor: I. Pecht

Received 14 June 2007, accepted 4 October 2007.


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