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Role of Interleukin-1ß in Activating the CD11c^high CD45RB^– Dendritic Cell Subset and Priming Leishmania amazonensis- Specific CD4⁺ T Cells In Vitro and In Vivo ^,

Department of Microbiology and Immunology,¹ Department of Pathology, Center for Biodefense and Emerging Infectious Diseases, Sealy Center for Vaccine Development, Institute for Human Infections and Immunity, University of Texas Medical Branch Galveston, Texas,³ Department of Infectious Diseases, Harbin Medical University, Harbin, Hei Long Jiang Province, China²

Received 6 April 2007/ Returned for modification 14 May 2007/ Accepted 28 July 2007

Cutaneous leishmaniasis associated with Leishmania amazonensis infection is characterized by uncontrolled parasite replication and profound immunosuppression; however, the underlying mechanisms remain largely unclear. One possibility is that the L. amazonensis parasite modulates antigen-presenting cells, favoring the generation of pathogenic Th cells that are capable of recruiting leukocytes but insufficient to fully activate their microbicidal activities. To test this possibility, we infected bone marrow-derived dendritic cells (DCs) of C57BL/6 mice with L. amazonensis or Leishmania major promastigotes and assessed the activation of DC subsets and their capacity in priming CD4⁺ T cells in vitro. In comparison to L. major controls, L. amazonensis-infected DCs secreted lower levels of interleukin-1 (IL-1) and IL-1ß, were less potent in activating the IL-12p40-producing CD11c^high CD45RB^– CD83⁺ CD40⁺ DC subset, and preferentially activated CD4⁺ T cells with a IFN-^low IL-10^high IL-17^high phenotype. Although the addition of IL-1ß at the time of infection markedly enhanced DC activation and T-cell priming, it did not skew the cytokine profile of DCs and pathogenic Th cells, as local injection of IL-1ß following L. amazonensis infection accelerated Th cell activation and disease progression. This study suggests that intrinsic defects at the level of DC activation are responsible for the susceptible phenotype in L. amazonensis-infected hosts and that this parasite may have evolved unique mechanisms to interfere with innate and adaptive immunity.

Published ahead of print on 6 August 2007.

Supplemental material for this article may be found at http://iai.asm.org/.

Editor: W. A. Petri, Jr.

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