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© The Rockefeller University Press, 0022-1007/1999/4/1111/ $5.00
The Journal of Experimental Medicine, Volume 189, Number 7, April 5, 1999 1111-1120

Articles

Altered Ligands Reveal Limited Plasticity in the T Cell Response to a Pathogenic Epitope

Sabine Pingel*, Pascal Launois*,§, Deborah J. Fowell*, Christoph W. Turck*,{ddagger}, Scott Southwood||, Alessandro Sette||, Nicolas Glaichenhaus, Jacques A. Louis§, and Richard M. Locksley*,{ddagger}

From the * Departments of Medicine, Microbiology, and Immunology and the {ddagger} Howard Hughes Medical Institute, University of California San Francisco, San Francisco, California 94143; § World Health Organization Immunology Research and Training Center, Institute of Biochemistry, University of Lausanne, Epalinges CH-1066, Switzerland; || Cytel Corporation, San Diego, California 92121; and the Institute of Molecular and Cellular Pharmacology, University of Nice, Valbonne 06560, France

Experimental leishmaniasis offers a well characterized model of T helper type 1 cell (Th1)-mediated control of infection by an intracellular organism. Susceptible BALB/c mice aberrantly develop Th2 cells in response to infection and are unable to control parasite dissemination. The early CD4+ T cell response in these mice is oligoclonal and reflects the expansion of Vβ4/ V{alpha}8-bearing T cells in response to a single epitope from the parasite Leishmania homologue of mammalian RACK1 (LACK) antigen. Interleukin 4 (IL-4) generated by these cells is believed to direct the subsequent Th2 response. We used T cells from T cell receptor–transgenic mice expressing such a Vβ4/V{alpha}8 receptor to characterize altered peptide ligands with similar affinity for I-Ad. Such altered ligands failed to activate IL-4 production from transgenic LACK-specific T cells or following injection into BALB/c mice. Pretreatment of susceptible mice with altered peptide ligands substantially altered the course of subsequent infection. The ability to confer a healer phenotype on otherwise susceptible mice using altered peptides that differed by a single amino acid suggests limited diversity in the endogenous T cell repertoire recognizing this antigen.

Key Words: Leishmania major • CD4+ T cell subsets • altered peptide ligands • LACK antigen

Address correspondence to Richard M. Locksley, UCSF, Box 0654, C-443, 521 Parnassus Ave., San Francisco, CA 94143. Phone: 415-476-5859; Fax: 415-476-9364; E-mail: locksley{at}medicine.ucsf.edu or Jacques A. Louis, WHO Research and Training Center, University of Lausanne, Epalinges, Switzerland. Phone: 41-21-692-5703; Fax: 41-21-692-5705; E-mail: jacques.louis{at}ib.unil.ch

S. Pingel and P. Launois contributed equally to this work.

Abbreviations used: ABLE, LACK T cell receptor–specific transgenic; CDR3, complementarity determining region 3; LACK, Leishmania homologue of mammalian RACK1; RT, reverse transcriptase; TCR-C{alpha}0, T cell receptor constant region-{alpha}–deficient.


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