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

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^hiCD44^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^hipanCD44^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 ^hipanCD44^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.-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.