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In BALB/c Mice, IL-4 Production During the Initial Phase of Infection with Leishmania major Is Necessary and Sufficient to Instruct Th2 Cell Development Resulting in Progressive Disease¹

Hayo Himmelrich^*, Pascal Launois^2,*, Ivan Maillard, Tilo Biedermann^§, Fabienne Tacchini-Cottier^*, Richard M. Locksley, Martin Röcken^3,§ and Jacques A. Louis^5,*

^* World Health Organization Immunology Research and Training Center, Institute of Biochemistry, University of Lausanne, Epalinges, Switzerland; Institute of Microbiology, University of Lausanne, Lausanne, Switzerland, Departments of Medicine and Microbiology/Immunology and the Howard Hughes Medical Institute, University of California, San Francisco, CA 94143; and ^§ Department of Dermatology, Ludwig Maximilian University, Munich, Germany

In contrast to intact BALB/c mice, BALB/c mice rendered deficient in Vß4⁺ CD4⁺ T cells develop a Th1 response to infection with Leishmania major and are resistant. Vß4-deficient BALB/c mice are unable to generate the early IL-4 transcription occurring in Vß4 V8 CD4⁺ T cells of BALB/c mice within 1 day of infection. Here we demonstrate that treatment of Vß4-deficient BALB/c mice with IL-4 during the first 64 h after infection instructs Th2 cell development and susceptibility to infection. The demonstrated inability of IL-4 to reverse the resistant phenotype of BALB/c mice treated with anti-CD4 mAb the day before infection suggest that these effects of IL-4 require its interaction with CD4⁺ T cells. In contrast to draining lymph node cells from BALB/c mice, cells from Vß4-deficient BALB/c mice remain responsive to IL-12 following infection. Strikingly, administration of IL-4 to Vß4-deficient BALB/c mice renders their lymph node cells unresponsive to IL-12 by down-regulating IL-12R ß2-chain expression. This study directly demonstrates that in BALB/c mice IL-4 is necessary and sufficient to initiate the molecular events steering Th2 cell maturation and susceptibility to L. major.