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J Immunol. 2015 Oct 1;195(7):3218-26. doi: 10.4049/jimmunol.1500922. Epub 2015 Aug 24.

Interaction of Macrophage Antigen 1 and CD40 Ligand Leads to IL-12 Production and Resistance in CD40-Deficient Mice Infected with Leishmania major.

Author information

1
Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba R3E 0J9, Canada; and.
2
Department of Immunology, University of Manitoba, Winnipeg, Manitoba R3E 0T5, Canada.
3
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.

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.

PMID:
26304989
DOI:
10.4049/jimmunol.1500922
[Indexed for MEDLINE]
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