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Leishmania Major with Resistance in CD40-Deficient Mice Infected CD40

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Leishmania Major with Resistance in CD40-Deficient Mice Infected CD40 Interaction of Macrophage Antigen 1 and CD40 Ligand Leads to IL-12 Production and Resistance in CD40-Deficient Mice Infected with Leishmania major This information is current as of September 30, 2021. Ifeoma Okwor, Ping Jia and Jude E. Uzonna J Immunol 2015; 195:3218-3226; Prepublished online 24 August 2015; doi: 10.4049/jimmunol.1500922 http://www.jimmunol.org/content/195/7/3218 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2015/08/21/jimmunol.150092 Material 2.DCSupplemental http://www.jimmunol.org/ References This article cites 46 articles, 22 of which you can access for free at: http://www.jimmunol.org/content/195/7/3218.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 30, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2015 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Interaction of Macrophage Antigen 1 and CD40 Ligand Leads to IL-12 Production and Resistance in CD40-Deficient Mice Infected with Leishmania major Ifeoma Okwor,* Ping Jia,† and Jude E. Uzonna*,† 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 Downloaded from cessation of rIL-12 treatment. Disease reactivation in CD40L KO mice was associated with impaired IL-12 and IFN-g 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-g response and loss of infection-induced immunity after secondary L. major challenge. Collectively, our data reveal a novel role of CD40L–Mac-1 http://www.jimmunol.org/ interaction in IL-12 production, development, and maintenance of optimal Th1 immunity in mice infected with L. major. The Journal of Immunology, 2015, 195: 3218–3226. umerous studies have shown that CD40–CD40L inter- infections. Interestingly, some studies suggest that CD40–CD40L action is essential for induction of effective cell-mediated interaction is not required for protection against L. major (8, 9). In N immunity to pathogens. CD40 is constitutively expressed addition, blockade of CD40–CD40L interaction in patients with on basophils, dendritic cells (DCs), B cells, and epithelial cells but cutaneous leishmaniasis due to Leishmania braziliensis did not can be induced on macrophages, endothelial cells, smooth muscle affect IFN-g production by T cells or progression of cutaneous + cells, and fibroblasts. CD40L, in contrast, is inducible on CD4 and lesion. Thus, the role of CD40–CD40L interaction in leishmaniasis by guest on September 30, 2021 CD8+ T cells, B cells, epithelial cells, eosinophils, monocytes, remains controversial and needs to be further delineated. macrophages, NK cells, and mast cells (1). Previous reports show Macrophage Ag 1 (Mac-1) is a b2 integrin that is present on that CD40–CD40L interaction is critical for the production of monocytes, neutrophils, and macrophages (10), and it plays an IL-12 and induction of optimal Th1 response and immunity to essential role in immunity by influencing adhesion and migration cutaneous leishmaniasis (2). Treatment of the susceptible BALB/c of phagocytic cells (11). It is composed of two chains, CD18 and mice with CD40 agonistic Ab led to healing postinfection with CD11b, a type 1 transmembrane receptor composed of extracel- Leishmania major (3). In contrast, injection of anti-CD40L antago- lular, transmembrane, and cytoplasmic domains (12). The cyto- nists led to susceptibility in the resistant C57BL/6, which was plasmic domain of CD11b is believed to be important for re- associated with reduced IL-12 production (4). Furthermore, defi- cognition of pathogen-associated molecular patterns such as ciency of CD40L or CD40 in the usually resistant C57BL/6 leads Mycobacterium tuberculosis oligosaccharides and Leishmania to susceptibility to L. major (5, 6) and Leishmania amazonensis (7) lipophosphoglycan (13). In contrast, the I domain near the N- terminal region is responsible for binding C3bi, fibrinogen, and other bacterial Ag (14). The binding ability of the C and I domains *Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba could explain the wide range of ligands bound by Mac-1 (14, 15). R3E 0J9, Canada; and †Department of Immunology, University of Manitoba, Winni- peg, Manitoba R3E 0T5, Canada Recent reports show that, in the absence of CD40, Mac-1 can bind Received for publication April 20, 2015. Accepted for publication July 28, 2015. to CD40L and mediate the production of proinflammatory cyto- kine leading to inflammation (10). However, whether Mac-1 can This work was supported by the Canadian Institutes for Health Research (CIHR; to J.E.U.), Research Manitoba (to J.E.U.), a CIHR-Frederic Banting and Charles Best bind to CD40L and regulate the outcome of immunity to L. major Doctoral Award (to I.O.), and the CIHR-International Infectious Disease and Global has not yet been determined. Health Training Program (I.O.). In this article, we compared the immune response and outcome Address correspondence and reprint requests to Dr. Jude E. Uzonna, Department of of L. major infection in CD40 and CD40L knockout (KO) mice Immunology, College of Medicine, University of Manitoba, 750 McDermot Avenue, Winnipeg, MB R3E 0T5, Canada. E-mail address: [email protected] and investigated the role of Mac-1–CD40L interaction in protec- The online version of this article contains supplemental material. tive immune response to L. major. Our data reveal striking dif- Abbreviations used in this article: BMDC, bone marrow–derived DC; BMDM, bone ferences in disease progression and immune response in IL- marrow–derived macrophage; DC, dendritic cell; DTH, delayed-type hypersensitiv- 12–treated CD40 and CD40L KO mice infected with L. major. ity; KO, knockout; Mac-1, macrophage Ag 1; SLA, soluble Leishmania Ag; WT, Whereas rIL-12–treated CD40 KO mice remained healed, devel- wild type. oped long-term immunity, and were resistant to secondary L. major Copyright Ó 2015 by The American Association of Immunologists, Inc. 0022-1767/15/$25.00 challenge, rIL-12–treated CD40L KO reactivated their lesion after www.jimmunol.org/cgi/doi/10.4049/jimmunol.1500922 The Journal of Immunology 3219 cessation of treatment. We show that these differences in disease Cytokine ELISAs pathogenesis were related, in part, to alternative utilization of IL-12p40, IFN-g, and IL-4 concentrations in cell culture supernatant fluids CD40L–Mac-1 pathway for continuous and sustained IL-12 were measured by sandwich ELISA using Ab pairs from BD Pharmingen production in CD40 KO mice. Thus, our studies reveal a criti- (San Jose, CA) according to manufacturer’s suggested protocols. The cal but redundant role of Mac-1–CD40L interaction in IL-12 hybridoma clones for the Ab pairs are: IL-12p40, C15.6 and C17.8; IFN-g, production and maintenance of optimal immunity to L. major R4-6A2 and XMG1.2; and IL-4, 11B11 and BVD6-24G2. infection. Generation of bone marrow–derived DCs and bone marrow– derived macrophages Materials and Methods Bone marrow–derived DCs (BMDCs) and bone marrow–derived macro- Mice phages (BMDMs) were generated from naive WT, CD40, and CD40L KO mice as described previously (17). In brief, bone marrow cells were iso- Six- to eight-week-old female wild type (WT) C57BL/6 mice were purchased from Charles River Laboratories (St-Constante, QC, Canada). CD40- and lated from the femur and tibia of mice and differentiated into macrophages CD40L-deficient mice on C57BL/6 background were purchased from The using complete medium supplemented with 30% L929 cell culture su- Jackson Laboratory (Sacramento, CA). Mice were housed in specific pernatant. BMDCs were differentiated in petri dishes in the presence of pathogen-free units at the Central Animal Care Services, University of 20 ng/ml rGM-CSF (Peprotech, Rocky Hill, NJ). Immature DCs were Manitoba. All
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