title: Reduction of CD18 promotes expansion of inflammatory γδ T cells collaborating with CD4+ T cells in chronic murine psoriasiform dermatitis.
abstract: IL-17 is a critical factor in the pathogenesis of psoriasis and other inflammatory diseases. The impact of γδ T cells, accounting for an important source of IL-17 in acute murine IL-23- and imiquimod-induced skin inflammation, in human psoriasis is still unclear. Using the polygenic CD18(hypo) PL/J psoriasis mouse model spontaneously developing chronic psoriasiform dermatitis due to reduced CD18/β2 integrin expression to 2-16% of wild-type levels, we investigated in this study the influence of adhesion molecule expression on generation of inflammatory γδ T cells and analyzed the occurrence of IL-17-producing γδ and CD4(+) T cells at different disease stages. Severity of CD18(hypo) PL/J psoriasiform dermatitis correlated with a loss of skin-resident Vγ5(+) T cells and concurrent skin infiltration with IL-17(+), IL-22(+), and TNF-α(+) γδTCR(low) cells preceded by increases in Vγ4(+) T cells in local lymph nodes. In vitro, reduced CD18 levels promoted expansion of inflammatory memory-type γδ T cells in response to IL-7. Similar to IL-17 or IL-23/p19 depletion, injection of diseased CD18(hypo) PL/J mice with anti-γδTCR Abs significantly reduced skin inflammation and largely eliminated pathological γδ and CD4(+) T cells. Moreover, CD18(hypo) γδ T cells induced allogeneic CD4(+) T cell responses more potently than CD18(wt) counterparts and, upon adoptive transfer, triggered psoriasiform dermatitis in susceptible hosts. These results demonstrate a novel function of reduced CD18 levels in generation of pathological γδ T cells that was confirmed by detection of increases in CD18(low) γδ T cells in psoriasis patients and may also have implications for other inflammatory diseases.
authors.affiliation: Department of Dermatology and Allergic Diseases, University of Ulm, Ulm 89081, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Gatzka
authors.forename: Adelheid
authors.initials: A
authors.lastname: Hainzl
authors.forename: Thorsten
authors.initials: T
authors.lastname: Peters
authors.forename: Kamayani
authors.initials: K
authors.lastname: Singh
authors.forename: Alpaslan
authors.initials: A
authors.lastname: Tasdogan
authors.forename: Meinhard
authors.initials: M
authors.lastname: Wlaschek
authors.forename: Karin
authors.initials: K
authors.lastname: Scharffetter-Kochanek
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D018821:CD18 Antigens / Q000235:genetics / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002450:Cell Communication; D049109:Cell Proliferation; D002478:Cells, Cultured; D002908:Chronic Disease; D016207:Cytokines / Q000276:immunology; D003872:Dermatitis / Q000276:immunology*; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D015536:Down-Regulation; D006801:Humans; D018836:Inflammation Mediators / Q000276:immunology; D051379:Mice; D008815:Mice, Inbred Strains; D011565:Psoriasis / Q000276:immunology*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology*
chemical_list: D018821:CD18 Antigens; D016207:Cytokines; D018836:Inflammation Mediators; D016692:Receptors, Antigen, T-Cell, gamma-delta