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.

miR-21 Expression Determines the Early Vaccine Immunity Induced by LdCen−/− Immunization

“…Differences in L. major and L. donovani infections with respect to expression of IRF2, IRF7 , and IFIT5 was also reported analogous to the IL - 12p40 gene expression elicited by these two parasite species (38). Similarly, in L. major infections, ligation of CD40-CD40L, and macrophage antigen-1 (Mac-1)-CD40L interaction have been shown to induce IL-12 production (39). In this study we explored an additional mechanism of regulation of IL-12 by miR-21 that is used by the Leishmania parasite.…”

CD40 Generation 2.5 Antisense Oligonucleotide Treatment Attenuates Doxorubicin-induced Nephropathy and Kidney Inflammation

“…Additionally, studies are also needed to clarify the dependency of CD40L in the context of CD40 inhibition, as reports have established non-canonical pathways of CD40L signaling that do not involve CD40 (refs. 33,34,35,36). Finally, studies to precisely determine the relative potency of ASOs across unique cell populations that reside in the renal cortex during disease will be an important advance in defining the therapeutic potential of the Generation 2.5 chemistry platform for chronic kidney disease.…”

CD154 inhibits death of T cells via a Cis interaction with the α5β1 integrin

“…In addition to CD40, sCD154 was shown to bind other receptors, namely the αIIbβ3 [ 21 ], αMβ2 (Mac-1) [ 22 ], α5β1 [ 23 ] and αvβ3 integrins [ 24 ]. The interaction of sCD154 with αIIbβ3 on platelets was shown to stabilize thrombus under high sheer conditions [ 25 ], while that with αMβ2 was reported to promote the development of inflammation in the vessels and atherosclerosis [ 22 ], and to play a role in Th1 immune responses against Leishmania major infections [ 26 ]. The αvβ3 integrin was identified as a receptor for CD154.…”