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) 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 Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Micheletti, F. Articles by Gavioli, R. Search for Related Content PubMed PubMed Citation Articles by Micheletti, F. Articles by Gavioli, R.

Supra-Agonist Peptides Enhance the Reactivation of Memory CTL Responses¹

Fabiola Micheletti^*, Alessandro Canella^*, Simona Vertuani^*, Mauro Marastoni, Lara Tosi, Stefano Volinia, Serena Traniello^* and Riccardo Gavioli^2,*

^* Departments of Biochemistry and Molecular Biology, Pharmaceutical Sciences, and Morphology and Embryology, University of Ferrara, Ferrara, Italy

Single amino acid substitutions at TCR contacts may transform a natural peptide Ag in CTL ligands with partial agonist, antagonist, or null activity. We obtained peptide variants by changing nonanchor amino acid residues involved in MHC class I binding. These peptides were derived from a subdominant HLA-A2-presented, latent membrane protein 2-derived epitope expressed in EBV-infected cells and in EBV-associated tumors. We found that small structural changes produced ligands with vastly different activities. In particular, the variants that associated more stably to HLA-A2/molecules did not activate any CTL function, behaving as null ligands. Interestingly, T cell stimulations performed with the combination of null ligands and the natural epitope produced significantly higher specific CTL reactivation than reactivation of CTLs induced by the wild-type epitope alone. In addition, these particular variants activated memory CTL responses in the presence of concentrations of natural epitope that per se did not induce T cell responses. We show here that null ligands increased ZAP-70 tyrosine kinase activation induced by the natural epitope. Our results demonstrate for the first time that particular peptide variants, apparently behaving as null ligands, interact with the TCR, showing a supra-agonist activity. These variant peptides did not affect the effector T cell functions activated by the natural epitope. Supra-agonist peptides represent the counterpart of antagonists and may have important applications in the development of therapeutic peptides.

This article has been cited by other articles:

				K. Takada and S. C. Jameson Self-class I MHC molecules support survival of naive CD8 T cells, but depress their functional sensitivity through regulation of CD8 expression levels J. Exp. Med., September 28, 2009; 206(10): 2253 - 2269. [Abstract] [Full Text] [PDF]

				R. Gavioli, E. Gallerani, C. Fortini, M. Fabris, A. Bottoni, A. Canella, A. Bonaccorsi, M. Marastoni, F. Micheletti, A. Cafaro, et al. HIV-1 Tat Protein Modulates the Generation of Cytotoxic T Cell Epitopes by Modifying Proteasome Composition and Enzymatic Activity J. Immunol., September 15, 2004; 173(6): 3838 - 3843. [Abstract] [Full Text] [PDF]

				A. Castilleja, D. Carter, C. L. Efferson, N. E. Ward, K. Kawano, B. Fisk, A. P. Kudelka, D. M. Gershenson, J. L. Murray, C. A. O'Brian, et al. Induction of Tumor-Reactive CTL by C-Side Chain Variants of the CTL Epitope HER-2/neu Protooncogene (369-377) Selected by Molecular Modeling of the Peptide: HLA-A2 Complex J. Immunol., October 1, 2002; 169(7): 3545 - 3554. [Abstract] [Full Text] [PDF]