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This Article Full Text Full Text (PDF) All Versions of this Article: jimmunol.0901319v1 183/8/5190    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Chung, J.-S. Articles by Ariizumi, K. PubMed PubMed Citation Articles by Chung, J.-S. Articles by Ariizumi, K.

Binding of DC-HIL to Dermatophytic Fungi Induces Tyrosine Phosphorylation and Potentiates Antigen Presenting Cell Function¹

Jin-Sung Chung,^* Tatsuo Yudate, Mizuki Tomihari,^* Hideo Akiyoshi,^* Ponciano D. Cruz, Jr.,^* and Kiyoshi Ariizumi^2*

^*Department of Dermatology, The University of Texas Southwestern Medical Center and; the Dermatology Section (Medical Service), Dallas Veterans Affairs Medical Center; Dallas, Texas 75390; Department of Dermatology, Kinki University School of Medicine, Osaka-Sayama, Osaka, Japan; Osaka Prefecture University, Graduate School of Life and Environmental Science, Veterinary Medical Science, Sakai-shi, Osaka, Japan; and Department of Clinical Veterinary Medicine, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Japan

APCs express receptors recognizing microbes and regulating immune responses by binding to corresponding ligands on immune cells. Having discovered a novel inhibitory pathway triggered by ligation of DC-HIL on APC to a heparin/heparan sulfate-like saccharide of syndecan-4 on activated T cells, we posited DC-HIL can recognize microbial pathogens in a similar manner. We showed soluble recombinant DC-HIL to bind the dermatophytes Trichophyton rubrum and Microsporum audouinii, but not several bacteria nor Candida albicans. Dermatophyte binding was inhibited completely by the addition of heparin. Because DC-HIL contains an ITAM-like intracellular sequence, we questioned whether its binding to dermatophytes can induce tyrosine phosphorylation in dendritic cells (DC). Culturing DC with T. rubrum (but not with C. albicans pseudohyphae) induced phosphorylation of DC-HIL, but not when the tyrosine residue of the ITAM-like sequence was mutated to phenylalanine. To examine the functional significance of such signaling on DC, we cross-linked DC-HIL with mAb (surrogate ligand), which not only induced tyrosine phosphorylation but also up-regulated expression of 23 genes among 662 genes analyzed by gene-array, including genes for profilin-1, myristoylated alanine rich protein kinase C substrate like-1, C/EBP, LOX-1, IL-1β, and TNF-. This cross-linking also up-regulated expression of the activation markers CD80/CD86 and heightened APC capacity of DC to activate syngeneic T cells. Our findings support a dual role for DC-HIL: inhibition of adaptive immunity following ligation of syndecan-4 on activated T cells and induction of innate immunity against dermatophytic fungi.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the National Institutes of Health (A164927-01) and from Galderma.

² Address correspondence and reprint requests to Dr. Kiyoshi Ariizumi, University of Texas, 5323 Harry Hines Blvd., Dallas, TX 75390-9069. E-mail address: kiyoshi.ariizumi{at}utsouthwestern.edu

³ Abbreviations used in this paper: DC, dendritic cell; LC, Langerhans cell; PRR, pattern recognition receptor; SD-4, syndecan-4; BM, bone marrow; HS, heparin/heparan sulfate; Marcksl-1, myristoylated alanine rich protein kinase C substrate like-1; PD-1, programmed cell death-1.