title: Targeted activation of CD8 cells and infection of beta 2-microglobulin-deficient mice fail to confirm a primary protective role for CD8 cells in experimental leishmaniasis.
abstract: CD8+ T cells play an important role in the immunologic control of intracellular pathogens, particularly viruses. Leishmania are obligate intracellular parasites of macrophages in the mammalian host, and previous studies using deletion of CD8+ cells by administration of mAb to infected animals have suggested a protective role for these cells. Two complementary approaches were used to define more carefully the role of CD8+ cells in leishmaniasis. In BALB/c mice susceptible to Leishmania major (L. major) infection, targeted activation of CD8+ T cells was attempted by immunization with nonapeptides derived from the conserved major outer surface protein of the organism, gp63, that contained the consensus binding motif for MHC class I H-2Kd molecules. Two of the nonapeptides induced CTL activity in subsequently infected BALB/c mice that could be elicited against P815 cells pulsed either with peptide or lysates of L. major. Purified CD8+ T cells from immunized mice had elevated levels of IFN-gamma mRNA transcripts as compared to unimmunized mice. Despite evidence for activation of CD8+ cells, none of the mice immunized with nine different peptides alone or in combination were protected from progressive disease. In a second series of experiments, beta 2-microglobulin deficient mice that lack CD8+ cells were infected with L. major and the course of infection monitored. These mice cured disease as rapidly as beta 2-m +/- and +/+ littermates, and cure was associated with comparable levels of IFN-gamma mRNA in the draining lymph node population. Neither of these approaches was able to confirm a substantive role for CD8+ T cells in the primary protective response to L. major.
authors.affiliation: Department of Medicine, UCSF 94143-0654.
authors.forename: Z E
authors.initials: ZE
authors.lastname: Wang
authors.forename: S L
authors.initials: SL
authors.lastname: Reiner
authors.forename: F
authors.initials: F
authors.lastname: Hatam
authors.forename: F P
authors.initials: FP
authors.lastname: Heinzel
authors.forename: J
authors.initials: J
authors.lastname: Bouvier
authors.forename: C W
authors.initials: CW
authors.lastname: Turck
authors.forename: R M
authors.initials: RM
authors.lastname: Locksley
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D016827:CD8 Antigens / Q000032:analysis; D016207:Cytokines / Q000235:genetics; D005260:Female; D007114:Immunization; D007895:Leishmania tropica / Q000276:immunology*; D016773:Leishmaniasis, Cutaneous / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D009838:Oligodeoxyribonucleotides / Q000737:chemistry; D010455:Peptides / Q000737:chemistry / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D001613:beta 2-Microglobulin / Q000235:genetics
chemical_list: D016827:CD8 Antigens; D016207:Cytokines; D009838:Oligodeoxyribonucleotides; D010455:Peptides; D001613:beta 2-Microglobulin