title: The immunologic significance of variation within malaria circumsporozoite protein sequences.
abstract: We have previously suggested that variation within the circumsporozoite protein of the malaria parasite Plasmodium falciparum was the result of selection by immune T cells. Our hypothesis has been supported by experiments documenting a lack of cross-reactivity between variant peptides from the C-terminal region for murine T cells primed by 7G8-specific sequences. Now, by using a murine model we have found that peptides representing variant regions (amino acid residues 326-343 and 361-380) of two other parasite clones (Wel and LE5) are also immunodominant for murine T cells. However, there were distinct changes in response profiles. For example, whereas lymph node cells from H-2d and H mice immunized with peptides from the 326-343 region of all three variants proliferated in vitro after homologous challenge, only lymph node cells from H-2b mice immunized with LE5 peptide proliferate after homologous challenge. In contrast, only LE5 did not induce lymphoproliferation against homologous challenge in the H-2s background. These data suggest that the naturally occurring substitutions affect agretopic (i.e., Ia). Peptides from all variants representing the 361-380 domain were recognized only by T cells from H-2k mice. Also, in nearly all cases, T cells primed by one sequence did not recognize variant sequences. The immunodominance of these domains from three different clones and the lack of significant cross-reactivity further supports the hypothesis that variation is the result of T cell immune pressure.
authors.affiliation: Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892.
authors.forename: V F
authors.initials: VF
authors.lastname: De La Cruz
authors.forename: W L
authors.initials: WL
authors.lastname: Maloy
authors.forename: L H
authors.initials: LH
authors.lastname: Miller
authors.forename: M F
authors.initials: MF
authors.lastname: Good
authors.forename: T F
authors.initials: TF
authors.lastname: McCutchan
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000940:Antigenic Variation; D000953:Antigens, Protozoan / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D000954:Antigens, Surface / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000276:immunology; D010449:Peptide Mapping; D010963:Plasmodium falciparum / Q000235:genetics / Q000276:immunology*; D015800:Protozoan Proteins; D013045:Species Specificity; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology
chemical_list: D000953:Antigens, Protozoan; D000954:Antigens, Surface; D000949:Histocompatibility Antigens Class II; D010446:Peptide Fragments; D015800:Protozoan Proteins; C041595:circumsporozoite protein, Protozoan