Binding of DC-HIL to dermatophytic fungi induces tyrosine phosphorylation and potentiates antigen presenting cell function.
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-1beta, and TNF-alpha. 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.
Department of Dermatology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Jin-Sung
JS
Chung
Tatsuo
T
Yudate
Mizuki
M
Tomihari
Hideo
H
Akiyoshi
Ponciano D
PD
Cruz
Kiyoshi
K
Ariizumi
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology* / Q000382:microbiology; D001419:Bacteria / Q000276:immunology / Q000378:metabolism; D002176:Candida albicans / Q000276:immunology*; D003881:Dermatomycoses / Q000276:immunology* / Q000378:metabolism; D005136:Eye Proteins; D005260:Female; D015870:Gene Expression / Q000235:genetics / Q000276:immunology; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008864:Microsporum / Q000276:immunology*; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D011971:Receptors, Immunologic / Q000276:immunology*; D053671:Syndecan-4 / Q000276:immunology / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology / Q000382:microbiology; D014249:Trichophyton / Q000276:immunology*; D014443:Tyrosine / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
D005136:Eye Proteins; C445671:Gpnmb protein, mouse; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; D053671:Syndecan-4; D014443:Tyrosine