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for MHC Class I Reveals Mutants with Enhanced Binding1
,
* Department of Laboratory Medicine,
Section of Immunobiology, and
Department of Genetics, Yale University, New Haven, CT 06520
In an effective immune response, CD8+ T cell recognition of virally derived Ag, bound to MHC class I, results in killing of infected cells. The CD8
heterodimer acts as a coreceptor with the TCR, to enhance sensitivity of the T cells to peptide/MHC class I, and is two orders of magnitude more efficient as a coreceptor than the CD8. To understand the important interaction between CD8 and MHC class I, we created a panel of CD8 mutants and identified mutations in the CDR1, CDR2, and CDR3 loops that decreased binding to MHC class I tetramers as well as mutations that enhanced binding. We tested the coreceptor function of a subset of reducing and enhancing mutants using a T cell hybridoma and found similar reducing and enhancing effects. CD8-enhancing mutants could be useful for immunotherapy by transduction into T cells to enhance T cell responses against weak Ags such as those expressed by tumors. We also addressed the question of the orientation of CD8 with MHC class I using CD8 mutants expressed as a heterodimer with wild-type CD8 or CD8. The partial rescuing of binding with wild-type CD8 compared with wild-type CD8 is consistent with models in which either the topology of CD8 and CD8 binding to MHC class I is different or CD8 is capable of binding in both the T cell membrane proximal and distal positions.
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 National Institutes of Health Grant R01 CA048115 (to P.B.K.) and the Trudeau Fellowship at the Yale School of Medicine (to D.T.).
2 Address correspondence and reprint requests to Dr. Paula B. Kavathas, Section of Immunology, Yale University School of Medicine, Anlyan Center S641, 300 Cedar Street, P.O. Box 208011, New Haven, CT 06520-8011. E-mail address: Paula.Kavathas{at}yale.edu
3 Abbreviations used in this paper: pMHC I, peptide-MHC class I; MFI, mean fluorescence intensity; BI, binding index.
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