title: Perforin and gamma interferon are critical CD8+ T-cell-mediated responses in vaccine-induced immunity against Leishmania amazonensis infection.
abstract: Previous studies have demonstrated that protection against New World leishmaniasis caused by Leishmania amazonensis can be elicited by immunization with the developmentally regulated Leishmania amastigote antigen, P-8. In this study, several independent experimental approaches were employed to investigate the protective immunological mechanisms involved. T-cell subset depletion experiments clearly indicate that elicitation of CD8(+) (as well as CD4(+)) effector responses is required for protection. Further, mice lacking beta(2)-microglobulin (and hence deficient in major histocompatibility complex class I antigen presentation) were not able to control a challenge infection after vaccination, indicating an essential protective role for CD8(+) T effector responses. Analysis of the events ongoing at the cutaneous site of infection indicated a changing cellular dynamic involved in protection. Early postinfection in protectively vaccinated mice, a predominance of CD8(+) T cells, secreting gamma interferon (IFN-gamma) and expressing perforin, was observed at the site of infection; subsequently, activated CD4(+) T cells producing IFN-gamma were primarily found. As protection correlated with the ratio of total IFN-gamma-producing cells (CD4(+) and CD8(+) T cells) to macrophages found at the site of infection, a role for IFN-gamma was evident; in addition, vaccination of IFN-gamma-deficient mice failed to provide protection. To further assess the effector mechanisms that mediate protection, mice deficient in perforin synthesis were examined. Perforin-deficient mice vaccinated with the P-8 antigen were unable to control infection. Thus, the elicitation of CD8(+) T cell effector mechanisms (perforin, IFN-gamma) are clearly required in the protective immune response against L. amazonensis infection in vaccinated mice.
authors.affiliation: Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut 06520-8034, USA.
authors.forename: María
authors.initials: M
authors.lastname: Colmenares
authors.forename: Peter E
authors.initials: PE
authors.lastname: Kima
authors.forename: Erika
authors.initials: E
authors.lastname: Samoff
authors.forename: Lynn
authors.initials: L
authors.lastname: Soong
authors.forename: Diane
authors.initials: D
authors.lastname: McMahon-Pratt
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D005260:Female; D007371:Interferon-gamma / Q000502:physiology*; D007894:Leishmania mexicana / Q000276:immunology*; D016773:Leishmaniasis, Cutaneous / Q000517:prevention & control*; D008198:Lymph Nodes / Q000276:immunology; D008562:Membrane Glycoproteins / Q000276:immunology* / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D015800:Protozoan Proteins / Q000276:immunology*; D016052:Protozoan Vaccines / Q000276:immunology*; D014611:Vaccination
chemical_list: D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D015800:Protozoan Proteins; D016052:Protozoan Vaccines; D054353:Perforin; C066248:surface glycoprotein GP46-M-2, Leishmania; D007371:Interferon-gamma