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- Title
CD44 variant isoforms control experimental autoimmune encephalomyelitis by affecting the lifespan of the pathogenic T cells.
- Authors
Ghazi-Visser, Lizette; Laman, Jon D.; Nagel, Sabine; van Meurs, Marjan; van Riel, Debby; Tzankov, Alexandar; Frank, Stephan; Adams, Heiner; Wolk, Kerstin; Terracciano, Luigi; Melief, Marie-José; Sabat, Robert; Günthert, Ursula
- Abstract
CD44 variant (CD44v) 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 CD44v isoforms in MS and its animal model, experimental autoimmune encephalomyelitis (EAE). Genetic ablation of CD44v7 and CD44v10 isoforms significantly reduced the clinical EAE burden, as well as the number of inflammatory infiltrates. CD44v7 and CD44v10 expression on both memory T and antigen-presenting cells, participated in the development of adoptive transfer EAE. Significantly reduced mRNA expression of Thl signature genes was detected in the brains of CD44v10-/- mice compared with those of CD44WT mice. Furthermore, forkhead transcription factor 3 (Foxp3), Bcl-2, and inducible nitric oxide synthase (iNOS) levels were reduced in CD44v10-/- brains, whereas active caspase-3 was elevated. Brain-infiltrating CD4hiCD44v10+ T cells preceded EAE onset and paralleled disease severity in wild-type but not in CD44v7-/- and CD44v10-/- mice. CD44v7 and CD44v10 expression contributed to EAE by increasing the longevity of absence of CD44v7 and CD44v10 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 CD44v3, CD44v7, and CD44v10 isoforms on glial cells and on perivascular infiltrating cells of MS lesions. We conclude that CD44v7 and CD44v10, expressed on autoreactive CD4hlpanCD44hi T cells, are critically involved in the pathogenesis of classic EAE by increasing their life span. Targeting these short CD44v isoform regions may reduce inflammatory processes and clinical symptoms in MS.
- Subjects
ENCEPHALOMYELITIS; AUTOIMMUNE diseases; ANTIGEN presenting cells; NEUROGLIA; APOPTOSIS; T cells; FORKHEAD transcription factors
- Publication
FASEB Journal, 2013, Vol 27, Issue 9, p3683
- ISSN
0892-6638
- Publication type
Article
- DOI
10.1096/fj.13-228809