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J. Biol. Chem., Vol. 281, Issue 38, 28090-28096, September 22, 2006

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CD8 Has Two Distinct Binding Modes of Interaction with Peptide-Major Histocompatibility Complex Class I^*

Hsiu-Ching Chang¹, Kemin Tan, and Yen-Ming Hsu

From the Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115 and Molecular Discovery Department, Biogen-Idec, Inc., Cambridge, Massachusetts 02142

Interaction of CD8 (CD8 or CD8) with the peptide-major histocompatibility complex (MHC) class I (pMHCI) is critical for the development and function of cytolytic T cells. Although the crystal structure of CD8·pMHCI complex revealed that two symmetric CD8 subunits interact with pMHCI asymmetrically, with one subunit engaged in more extensive interaction than the other, the details of the interaction between the CD8 heterodimer and pMHCI remained unknown. The Ig-like domains of mouse CD8 and CD8 are similar in the size, shape, and surface electrostatic potential of their pMHCI-binding regions, suggesting that their interactions with pMHCI could be very similar. Indeed, we found that the CD8 variants CD8^R8A and CD8^E27A, which were functionally inactive as homodimers, could form an active co-receptor with wild-type (WT) CD8 as a CD8^R8A or CD8^E27A heterodimer. We also identified CD8 variants that could form active receptors with WT CD8 but not with CD8^R8A. This observation is consistent with the notion that the CD8 subunit may replace either CD8 subunit in CD8·pMHCI complex. In addition, we showed that both anti-CD8 and anti-CD8 antibodies were unable to completely block the co-receptor activity of WT CD8. We propose that CD8 binds to pMHCI in at least two distinguishable orientations.

Received for publication, May 23, 2006 , and in revised form, July 10, 2006.

^* This work was supported by National Institutes of Health Grant AI45789 and by the Claudia Adams Barr investigator award of Dana-Farber Cancer Institute (to H.-C. C.). 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 To whom correspondence should be addressed: Dana-Farber Cancer Inst., Harvard Medical School, 77 Ave. Louis Pasteur, HIM-442, Boston, MA 02115. Tel.: 617-632-4497; Fax: 617-632-3668; E-mail: hsiu-ching_chang{at}dfci.harvard.edu.

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