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J. Biol. Chem., Vol. 281, Issue 21, 14907-14917, May 26, 2006

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Major Histocompatibility Complex and T Cell Interactions of a Universal T Cell Epitope from Plasmodium falciparum Circumsporozoite Protein^*

Carlos Parra-López, J. Mauricio Calvo-Calle^¶1, Thomas O. Cameron^||, Luis E. Vargas, Luz Mary Salazar, Manuel E. Patarroyo, Elizabeth Nardin^¶, and Lawrence J. Stern^**2

From the Fundación Instituto de Inmunología de Colombia, Grupo Funcional Inmunología, Carrera 50 No. 26-00, Bogotá, Colombia, Universidad Nacional de Colombia, Facultad de Ciencias, Carrera 30 Calle 45, Bogotá, Colombia, the ^¶Department of Molecular Parasitology, New York University School of Medicine, New York, New York 10010, the ^||Department of Pathology, New York University Medical School, New York, New York 10016, and the ^**Department of Pathology and Biochemistry and the Department of Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01655

A 20-residue sequence from the C-terminal region of the circumsporozoite protein of the malaria parasite Plasmodium falciparum is considered a universal helper T cell epitope because it is immunogenic in individuals of many major histocompatibility complex (MHC) haplotypes. Subunit vaccines containing T^* and the major B cell epitope of the circumsporozoite protein induce high antibody titers to the malaria parasite and significant T cell responses in humans. In this study we have evaluated the specificity of the T^* sequence with regard to its binding to the human class II MHC protein DR4 (HLA-DRB1^*0401), its interactions with antigen receptors on T cells, and the effect of natural variants of this sequence on its immunogenicity. Computational approaches identified multiple potential DR4-binding epitopes within T^*, and experimental binding studies confirmed the following two tight binding epitopes: one located toward the N terminus (the T^*-1 epitope) and one at the C terminus (the T^*-5 epitope). Immunization of a human DR4 volunteer with a peptide-based vaccine containing the T^* sequence elicited CD4⁺ T cells that recognize each of these epitopes. Here we present an analysis of the immunodominant N-terminal epitope T^*-1. T^*-1 residues important for interaction with DR4 and with antigen receptors on T^*-specific T cells were mapped. MHC tetramers carrying DR4/T^*-1 MHC-peptide complexes stained and efficiently stimulated these cells in vitro. T^*-1 overlaps a region of the protein that has been described as highly polymorphic; however, the particular T^*-1 residues required for anchoring to DR4 were highly conserved in Plasmodium sequences described to date.

Received for publication, October 25, 2005 , and in revised form, February 27, 2006.

^* This work was supported by National Institutes of Health Grants RO1-AI-38996 (to L. J. S.), U19-AI-57319 (to L. J. S.), and RO1-AI-025035 (to E. N.). 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 Present address: Dept. of Pathology, University of Massachusetts Medical School, 55 Lake Ave. North, Worcester, MA 01655.

² To whom correspondence should be addressed: Dept. of Pathology, 55 Lake Ave. North, Worcester, MA 01655. Tel.: 508-856-1831; Fax: 508-856-0019; E-mail: lawrence.stern{at}umassmed.edu.

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