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Infection and Immunity, June 2000, p. 3403-3411, Vol. 68, No. 6
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

A Subdominant CD8+ Cytotoxic T Lymphocyte (CTL) Epitope from the Plasmodium yoelii Circumsporozoite Protein Induces CTLs That Eliminate Infected Hepatocytes from Culture

Eileen D. Franke,1,* Alessandro Sette,2 John Sacci Jr.,1,3 Scott Southwood,2 Giampietro Corradin,3 and Stephen L. Hoffman1

Naval Medical Research Center, Silver Spring,1 and University of Maryland, Baltimore,3 Maryland; Epimmune, San Diego, California2; and Institute of Biochemistry, University of Lausanne, Epalinges, Switzerland4

Received 24 September 1999/Returned for modification 19 November 1999/Accepted 15 March 2000

Previous studies indicated that the Plasmodium yoelii circumsporozoite protein (PyCSP) 57-70 region elicits T cells capable of eliminating infected hepatocytes in vitro. Herein, we report that the PyCSP58-67 sequence contains an H-2d binding motif, which binds purified Kd molecules in vitro with low affinity (3,267 nM) and encodes an H-2d-restricted cytotoxic T lymphocyte (CTL) epitope. Immunization of BALB/c mice with three doses of a multiple antigen peptide (MAP) construct containing four branches of amino acids 57 to 70 linked to a lysine-glycine core [MAP4(PyCSP57-70)] and Lipofectin as the adjuvant induced both T-cell proliferation and a peptide-specific CTL response that was PyCSP59-67 specific, H-2d restricted, and CD8+ T cell dependent. Immunization with either DNA encoding the PyCSP or irradiated sporozoites demonstrated that this CTL epitope is subdominant since it is not recognized in the context of whole CSP immunization. The biological relevance of this CTL response was underlined by the demonstration that it could mediate genetically restricted, CD8+- and nitric-oxide-dependent elimination of infected hepatocytes in vitro, as well as partial protection of BALB/c mice against sporozoite challenge. These findings indicate that subdominant epitopes with low major histocompatibility complex affinity can be used to engineer epitope-based vaccines and have implications for the selection of epitopes for subunit-based vaccines.

* Corresponding author. Mailing address: Naval Medical Research Center, Room 1W36A, 503 Robert Grant Ave., Silver Spring, MD 20910-7500. Phone: (301) 319-7667. Fax: (301) 319-7410. E-mail: VillasanteE{at}nmrc.navy.mil.

Infection and Immunity, June 2000, p. 3403-3411, Vol. 68, No. 6
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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