title: CD44 variant isoforms control experimental autoimmune encephalomyelitis by affecting the lifespan of the pathogenic T cells.
abstract: CD44 variant (CD44(v)) isoforms play important roles in the development of autoimmune disorders, including colitis and arthritis, but their role in multiple sclerosis (MS) has been explored only to a limited extent. We determined the functional relevance of CD44(v) isoforms in MS and its animal model, experimental autoimmune encephalomyelitis (EAE). Genetic ablation of CD44(v7) and CD44(v10) isoforms significantly reduced the clinical EAE burden, as well as the number of inflammatory infiltrates. CD44(v7) and CD44(v10) expression on both memory T and antigen-presenting cells, participated in the development of adoptive transfer EAE. Significantly reduced mRNA expression of Th1 signature genes was detected in the brains of CD44(v10-/-) mice compared with those of CD44(WT) mice. Furthermore, forkhead transcription factor 3 (Foxp3), Bcl-2, and inducible nitric oxide synthase (iNOS) levels were reduced in CD44(v10-/-) brains, whereas active caspase-3 was elevated. Brain-infiltrating CD4(hi)CD44(v10+) T cells preceded EAE onset and paralleled disease severity in wild-type but not in CD44(v7-/-) and CD44(v10-/-) mice. CD44(v7) and CD44(v10) expression contributed to EAE by increasing the longevity of autoreactive CD4(hi)panCD44(hi) T cells. Accordingly, the absence of CD44(v7) and CD44(v10) led to increased apoptosis in the inflammatory infiltrates and reduced Th1 responses, resulting in marked disease reduction. Although absent in noninflamed human brains, we detected CD44(v3), CD44(v7), and CD44(v10) isoforms on glial cells and on perivascular infiltrating cells of MS lesions. We conclude that CD44(v7) and CD44(v10), expressed on autoreactive CD4(hi)panCD44(hi) T cells, are critically involved in the pathogenesis of classic EAE by increasing their life span. Targeting these short CD44(v) isoform regions may reduce inflammatory processes and clinical symptoms in MS.
authors.affiliation: Department of Immunology, University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Lizette
authors.initials: L
authors.lastname: Ghazi-Visser
authors.forename: Jon D
authors.initials: JD
authors.lastname: Laman
authors.forename: Sabine
authors.initials: S
authors.lastname: Nagel
authors.forename: Marjan
authors.initials: M
authors.lastname: van Meurs
authors.forename: Debby
authors.initials: D
authors.lastname: van Riel
authors.forename: Alexandar
authors.initials: A
authors.lastname: Tzankov
authors.forename: Stephan
authors.initials: S
authors.lastname: Frank
authors.forename: Heiner
authors.initials: H
authors.lastname: Adams
authors.forename: Kerstin
authors.initials: K
authors.lastname: Wolk
authors.forename: Luigi
authors.initials: L
authors.lastname: Terracciano
authors.forename: Marie-José
authors.initials: MJ
authors.lastname: Melief
authors.forename: Robert
authors.initials: R
authors.lastname: Sabat
authors.forename: Ursula
authors.initials: U
authors.lastname: Günthert
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D009103:Multiple Sclerosis / Q000235:genetics / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism* / Q000473:pathology*; D018417:Th1 Cells / Q000378:metabolism
chemical_list: D018960:Hyaluronan Receptors; D020033:Protein Isoforms
keywords: Th1; apoptosis; multiple sclerosis