Identification of glucocorticoid-induced TNF receptor-related protein ligand on keratinocytes: ligation by GITR induces keratinocyte chemokine production and augments T-cell proliferation.
Glucocorticoid-induced tumor necrosis factor (TNF) receptor-related protein ligand (GITRL) is a recently described co-stimulatory molecule expressed by antigen-presenting cells (APCs). Activated keratinocytes are known to engage intraepithelial T cells through co-stimulatory molecules. This study investigated the expression and function of GITRL in resting keratinocytes. We showed by immunofluorescence and flow cytometry that keratinocytes from Balb/C and C57Bl/6 mice, as well as PAM 212 murine cell line keratinocytes and human epidermal keratinocytes (HEK), express cell-surface GITRL. Stimulation of murine skin biopsies and HEK with GITR fusion protein (GITR: Fc FP) resulted in mRNA induction for chemoattractants: cutaneous T-cell-attracting chemokine (CTACK), thymus and activation-regulated chemokine (TARC), IL-8, monocyte chemoattractant protein-1 (MCP-1), and murine beta-defensin 3 (MBD3). Immunofluorescent studies on mouse biopsies treated with GITR: Fc FP confirmed corresponding TARC and MCP-1 protein production by keratinocytes. Chemokine induction was shown to be NF-kappaB-mediated. T-cell proliferation was enhanced by the addition of keratinocytes. This was reversed by pretreatment with an anti-GITRL antibody. We conclude that keratinocytes express GITRL, and that through this important co-stimulatory molecule, they have the potential to influence T-cell numbers in the skin through chemokine production and through a direct cell-cell effect on T-cell proliferation.
Byrne
Aideen M
AM
Department of Pediatrics, National Jewish Health, Denver, Colorado, USA.
Goleva
Elena
E
Leung
Donald Y M
DY
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D002450:Cell Communication / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D002478:Cells, Cultured; D054414:Chemokine CCL17 / Q000235:genetics / Q000378:metabolism; D054425:Chemokine CCL27 / Q000235:genetics / Q000378:metabolism; D000078404:Epidermal Cells; D004817:Epidermis / Q000276:immunology; D053450:Glucocorticoid-Induced TNFR-Related Protein; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D007668:Kidney / Q000166:cytology; D008024:Ligands; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017475:Receptors, Nerve Growth Factor / Q000276:immunology / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D013154:Spleen / Q000166:cytology; D048069:Tumor Necrosis Factors / Q000276:immunology / Q000378:metabolism*
D000906:Antibodies; C499538:Ccl17 protein, mouse; C119538:Ccl27a protein, mouse; D054414:Chemokine CCL17; D054425:Chemokine CCL27; D053450:Glucocorticoid-Induced TNFR-Related Protein; D016209:Interleukin-8; D008024:Ligands; D016328:NF-kappa B; D012333:RNA, Messenger; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C106544:Tnfrsf18 protein, mouse; C478966:Tnfsf18 protein, mouse; D048069:Tumor Necrosis Factors