CD44 variant isoforms control experimental autoimmune encephalomyelitis by affecting the lifespan of the pathogenic T cells

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 CD44visoforms in MS and its animal model, experimental autoimmune encephalomyelitis (EAE). Genetic ablation of CD44v7and CD44v10isoforms significantly reduced the clinical EAE burden, as well as the number of inflammatory infiltrates. CD44v7and CD44v10expression 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 CD44v10-/-mice compared with those of CD44WTmice. 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. CD44v7and CD44v10expression contributed to EAE by increasing the longevity of autoreactive CD4hipanCD44hiT cells. Accordingly, the absence of CD44v7and CD44v10led 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 CD44v10isoforms on glial cells and on perivascular infiltrating cells of MS lesions. We conclude that CD44v7and CD44v10, expressed on autoreactive CD4hipanCD44hiT cells, are critically involved in the pathogenesis of classic EAE by increasing their life span. Targeting these short CD44visoform regions may reduce inflammatory processes and clinical symptoms in MS.-Ghazi-Visser, L., Laman, J. D., Nagel, S., van Meurs, M., van Riel, D., Tzankov, A., Frank, S., Adams, H., Wolk, K., Terracciano, L., Melief, M.-J., Sabat, R., Günthert, U. CD44 variant isoforms control experimental autoimmune encephalomyelitis by affecting the lifespan of the pathogenic T cells.

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