title: Reduced CD18 levels drive regulatory T cell conversion into Th17 cells in the CD18hypo PL/J mouse model of psoriasis.
abstract: Defective development and function of CD4(+)CD25(high+)Foxp3(+) regulatory T cells (Tregs) contribute to the pathogenesis of psoriasis and other autoimmune diseases. Little is known about the influence of adhesions molecules on the differentiation of Foxp3(+) Tregs into proinflammatory Th17 cells occurring in lesional skin and blood of psoriasis patients. In the CD18(hypo) PL/J mouse model of psoriasis, reduced expression of CD18/β2 integrin to 2-16% of wild-type levels is associated with progressive loss of Tregs, impaired cell-cell contact between Tregs and dendritic cells (DCs), as well as Treg dysfunction as reported earlier. In the present investigation, Tregs derived from CD18(hypo) PL/J mice were analyzed for their propensity to differentiate into IL-17-producing Th17 cells in vivo and in in vitro Treg-DC cocultures. Adoptively transferred CD18(hypo) PL/J Tregs were more inclined toward conversion into IL-17-producing Th17 cells in vivo in an inflammatory as well as noninflammatory environment compared with CD18(wt) PL/J Tregs. Addition of neutralizing Ab against CD18 to Treg-DC cocultures in vitro promoted conversion of CD18(wt) PL/J Tregs to Th17 cells in a dose-dependent manner similar to conversion rates of CD18(hypo) PL/J Tregs. Reduced thymic output of naturally occurring Tregs and peripheral conversion of Tregs into Th17 cells therefore both contribute to the loss of Tregs and the psoriasiform dermatitis observed in CD18(hypo) PL/J mice. Our data overall indicate that CD18 expression levels impact Treg development as well as Treg plasticity and that differentiation of Tregs into IL-17-producing Th17 cells is distinctly facilitated by a subtotal deficiency of CD18.
authors: Department of Dermatology and Allergic Diseases, University of Ulm, Ulm 89081, Germany.
authors: Kamayani
authors: K
authors: Singh
authors: Martina
authors: M
authors: Gatzka
authors: Thorsten
authors: T
authors: Peters
authors: Lisa
authors: L
authors: Borkner
authors: Adelheid
authors: A
authors: Hainzl
authors: Honglin
authors: H
authors: Wang
authors: Anca
authors: A
authors: Sindrilaru
authors: Karin
authors: K
authors: Scharffetter-Kochanek
mesh_terms: D000818:Animals; D018821:CD18 Antigens / Q000235:genetics* / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D006801:Humans; D016130:Immunophenotyping; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D011565:Psoriasis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*
chemical_list: D018821:CD18 Antigens