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(American Journal of Pathology. 2006;168:158-169.)
© 2006 American Society for Investigative Pathology

Interleukin-27R (WSX-1/T-Cell Cytokine Receptor) Gene-Deficient Mice Display Enhanced Resistance to Leishmania donovani Infection but Develop Severe Liver Immunopathology

Lucia E. Rosas^*, Anjali A. Satoskar, Kimberly M. Roth^*, Tracy L. Keiser^*, Joseph Barbi^*, Christopher Hunter, Frederic J. de Sauvage and Abhay R. Satoskar^*,¶

From the Department of Microbiology,^* the Department of Molecular Virology, Immunology, and Medical Genetics,^¶ and the Department of Pathology, Ohio State University, Columbus, Ohio; the Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; and the Department of Molecular Biology, Genentech, South San Francisco, California

The interleukin-27 (IL-27)/T-cell cytokine receptor (TCCR) pathway plays an important role in development of protective immunity against cutaneous leishmaniasis caused by Leishmania major. In this study, we analyzed the role of IL-27/TCCR pathway in the host defense against visceral leishmaniasis (VL) by monitoring the course of L. donovani infection in TCCR-deficient C57BL/6 (TCCR–/–) mice. TCCR–/– mice mounted a robust inflammatory response, produced high levels of pro-inflammatory cytokines, and developed severe liver pathology after L. donovani infection that eventually resolved. Interestingly, L. donovani-infected TCCR–/– mice controlled the parasite growth in their organs significantly faster than similarly infected TCCR+/+ mice. Adoptive cell transfer and cell depletion studies revealed that CD4⁺ T cells were involved in mediating liver immunopathology and controlling L. donovani growth in TCCR–/– mice. These results indicate that the IL-27/TCCR pathway is not essential for the induction of protective Th1 response during VL but is involved in mediating susceptibility to L. donovani. Additionally, the data demonstrate that although the IL-27/TCCR interaction limits the severity of liver inflammation during VL by controlling CD4⁺ T-cell activity, it is not required for the resolution of hepatic immunopathology.

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