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Rapid IL-4 Production by Leishmania Homolog of Mammalian RACK1-Reactive CD4⁺ T Cells in Resistant Mice Treated Once with Anti-IL-12 or -IFN- Antibodies at the Onset of Infection with Leishmania major Instructs Th2 Cell Development, Resulting in Nonhealing Lesions¹

Pascal Launois^2,*, Alain Gumy^*, Hayo Himmelrich^*, Richard M. Locksley, Martin Röcken and Jacques A. Louis^3,*

^* World Health Organization Immunology Research and Training Center, Institute of Biochemistry, 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

Rapid production of IL-4 by Leishmania homolog of mammalian RACK1 (LACK)-reactive CD4⁺ T cells expressing the V4-V8 TCR chains has been shown to drive aberrant Th2 cell development and susceptibility to Leishmania major in BALB/c mice. In contrast, mice from resistant strains fail to express this early IL-4 response. However, administration of either anti-IL-12 or -IFN- at the initiation of infection allows the expression of this early IL-4 response in resistant mice. In this work we show that Leishmania homolog of mammalian RACK1-reactive CD4⁺ T cells also expressing the V4-V8 TCR chains are the source of the early IL-4 response to L. major in resistant mice given anti-IL-12 or -IFN- Abs only at the onset of infection. Strikingly, these cells were found to be required for the reversal of the natural resistance of C57BL/6 mice following a single administration of anti-IL-12 or -IFN- Abs. Together these results suggest that a deficiency in mechanisms capable of down-regulating the early IL-4 response to L. major contributes to the exquisite susceptibility of BALB/c mice to L. major.

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