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Control of Leishmania major by a Monoclonal ß T Cell Repertoire¹

Steven L. Reiner^2,*, Deborah J. Fowell^,, Naomi H. Moskowitz^*, Kevin Swier^*, Daniel R. Brown^*, Charles R. Brown^*, Christoph W. Turck^,§, Phillip A. Scott2^¶, Nigel Killeen and Richard M. Locksley3^,,§

^* Department of Medicine, Committee on Immunology and Gwen Knapp Center for Lupus and Immunology Research, University of Chicago, Chicago, IL 60637; Departments of Medicine and Microbiology and Immunology, and ^§ Howard Hughes Medical Institute, University of California, San Francisco, CA 94143; and ^¶ Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104

Little is known regarding the diversity of the host T cell response that is required to maintain immunologic control of microbial pathogens. Leishmania major persist as obligate intracellular parasites within macrophages of the mammalian host. Immunity is dependent upon activation of MHC class II-restricted T cells to an effector state capable of restricting growth and dissemination of the organisms. We generated -ß Leishmania-specific (ABLE) TCR transgenic mice with MHC class II-restricted T cells that recognized an immunodominant Leishmania Ag designated LACK. Naive T cells from ABLE mice proliferated in vitro after incubation with recombinant LACK or with Leishmania-parasitized macrophages and in vivo after injection into infected mice. Infected ABLE mice controlled Leishmania infection almost as well as wild-type mice despite a drastic reduction in the T cell repertoire. ABLE mice were crossed to mice with disruption of the TCR constant region gene to create animals with a single ß T cell repertoire. Although mice deficient in all ß T cells (TCR-C^o mice) failed to control L. major, mice with a monoclonal ß T cell repertoire (ABLE TCR-C^o mice) displayed substantial control. The immune system is capable of remarkable efficiency even when constrained to recognition of a single epitope from a complex organism.