title: Interaction of Macrophage Antigen 1 and CD40 Ligand Leads to IL-12 Production and Resistance in CD40-Deficient Mice Infected with Leishmania major.
abstract: Although some studies indicate that the interaction of CD40 and CD40L is critical for IL-12 production and resistance to cutaneous leishmaniasis, others suggest that this pathway may be dispensable. In this article, we compared the outcome of Leishmania major infection in both CD40- and CD40L-deficient mice after treatment with rIL-12. We show that although CD40 and CD40L knockout (KO) mice are highly susceptible to L. major, treatment with rIL-12 during the first 2 wk of infection causes resolution of cutaneous lesions and control of parasite replication. Interestingly, although treated CD40 KO mice remained healed, developed long-term immunity, and were resistant to secondary L. major challenge, treated CD40L KO reactivated their lesion after cessation of rIL-12 treatment. Disease reactivation in CD40L KO mice was associated with impaired IL-12 and IFN-γ production and a concomitant increase in IL-4 production by cells from lymph nodes draining the infection site. We show that IL-12 production by dendritic cells and macrophages via CD40L-macrophage Ag 1 (Mac-1) interaction is responsible for the sustained resistance in CD40 KO mice after cessation of rIL-12 treatment. Blockade of CD40L-Mac-1 interaction with anti-Mac-1 mAb led to spontaneous disease reactivation in healed CD40 KO mice, which was associated with impaired IFN-γ response and loss of infection-induced immunity after secondary L. major challenge. Collectively, our data reveal a novel role of CD40L-Mac-1 interaction in IL-12 production, development, and maintenance of optimal Th1 immunity in mice infected with L. major.
authors: Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba R3E 0J9, Canada; and.
authors: Ifeoma
authors: I
authors: Okwor
authors: Department of Immunology, University of Manitoba, Winnipeg, Manitoba R3E 0T5, Canada.
authors: Ping
authors: P
authors: Jia
authors: Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba R3E 0J9, Canada; and Department of Immunology, University of Manitoba, Winnipeg, Manitoba R3E 0T5, Canada jude.uzonna@umanitoba.ca.
authors: Jude E
authors: JE
authors: Uzonna
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D019013:CD40 Antigens / Q000235:genetics* / Q000276:immunology; D023201:CD40 Ligand / Q000235:genetics* / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D053765:Interleukin-12 Subunit p35 / Q000096:biosynthesis / Q000276:immunology / Q000494:pharmacology*; D015847:Interleukin-4 / Q000096:biosynthesis / Q000276:immunology; D018320:Leishmania major / Q000276:immunology*; D016773:Leishmaniasis, Cutaneous / Q000276:immunology* / Q000469:parasitology / Q000473:pathology; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D016177:Macrophage-1 Antigen / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011994:Recombinant Proteins / Q000494:pharmacology; D012008:Recurrence; D018417:Th1 Cells / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; C508859:Il12a protein, mouse; D053765:Interleukin-12 Subunit p35; D016177:Macrophage-1 Antigen; D011994:Recombinant Proteins; D023201:CD40 Ligand; D015847:Interleukin-4; D007371:Interferon-gamma