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Infection and Immunity, June 2003, p. 3172-3182, Vol. 71, No. 6
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.6.3172-3182.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Perforin and Gamma Interferon Are Critical CD8+ T-Cell-Mediated Responses in Vaccine-Induced Immunity against Leishmania amazonensis Infection

María Colmenares, Peter E. Kima,{dagger} Erika Samoff, Lynn Soong,{ddagger} and Diane McMahon-Pratt*

Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut 06520-8034

Received 24 September 2002/ Returned for modification 7 January 2003/ Accepted 21 March 2003

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 ß2-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.

* Corresponding author. Mailing address: Department of Epidemiology & Public Health, Yale University School of Medicine, 60 College St., LEPH 715, New Haven, CT 06520-8034. Phone: (203) 785-4481. Fax: (203) 737-2921. E-mail: diane.mcmahon-pratt{at}yale.edu.

Editor: J. M. Mansfield

{dagger} Present address: Microbiology and Cell Science Department, University of Florida, Gainesville, Fla.

{ddagger} Present address: Departments of Microbiology & Immunology and Pathology, University of Texas Medical Branch, Galveston, TX 77555-1019.

Infection and Immunity, June 2003, p. 3172-3182, Vol. 71, No. 6
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.6.3172-3182.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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