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Infection and Immunity, August 2002, p. 3994-4001, Vol. 70, No. 8
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.8.3994-4001.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Leishmania Priming of Human Dendritic Cells for CD40 Ligand-Induced Interleukin-12p70 Secretion Is Strain and Species Dependent

Mary Ann McDowell,1,{dagger} Mary Marovich,1,{ddagger} Rosalia Lira,1,§ Michael Braun,2 and David Sacks1*

Laboratory of Parasitic Diseases,1 Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 208922

Received 7 January 2002/ Returned for modification 11 March 2002/ Accepted 30 April 2002

A major question in the study of leishmaniasis is what dictates clinical disease expression produced by different Leishmania species, i.e., cutaneous versus systemic and healing versus nonhealing. Animal models using a Leishmania species associated with self-limiting cutaneous disease (L. major) have revealed that protective immunity requires CD40/CD40 ligand (CD40L)-dependent, interleukin-12 (IL-12)-driven Th1 responses. We recently showed that L. major can prime human dendritic cells (DCs) for CD40L-triggered IL-12p70 secretion and that these cells can drive a Th1 response in autologous T cells from sensitized individuals. Here we show that in contrast to L. major, Leishmania species responsible for visceral disease (L. donovani), as well as species associated with persistent, cutaneous lesions and occasional systemic disease (L. tropica), did not induce CD40L-dependent IL-12p70 production, despite comparable levels of uptake by DCs. Up-regulated surface expression of CD40 did not correlate with IL-12p70 production, and appreciable CD40L-induced IL-12p40 secretion was observed in uninfected as well as infected DCs, regardless of species. Reverse transcription-PCR analysis confirmed that the production of heterodimeric IL-12 was limited by expression of IL-12p35 mRNA, which was dependent on both a microbial priming signal and CD40 engagement for its high-level induction. The intrinsic differences in the ability of Leishmania species to prime DCs for CD40L-dependent IL-12p70 secretion may account, at least in part, for the evolution of healing and nonhealing forms of leishmanial disease.

* Corresponding author. Mailing address: NIAID, Laboratory of Parasitic Diseases, Bldg. 4, Rm. 126, Center Dr. MSC 0425, Bethesda, MD 20892-0425. Phone: (301) 496-0577. Fax: (301) 480-3708. E-mail: dsacks{at}nih.gov.

Editor: J. M. Mansfield

{dagger} Present address: Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556.

{ddagger} Present address: U.S. Military HIV Research Program, Rockville, MD 20850.

§ Present address: Instituto de Fisiologia Celular, Universidad Nacional Autonoma de Mexico, 04510 Mexico City, Mexico.

Infection and Immunity, August 2002, p. 3994-4001, Vol. 70, No. 8
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.8.3994-4001.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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