The mechanisms leading to autoimmune and inflammatory diseases in the CNS have not been elucidated. The environmental triggers of the aberrant presence of CD4+ T cells in the CNS are not known. In this article, we report that abnormal β-catenin expression in T cells drives a fatal neuroinflammatory disease in mice that is characterized by CNS infiltration of T cells, glial activation, and progressive loss of motor function. We show that enhanced β-catenin expression in T cells leads to aberrant and Th1-biased T cell activation, enhanced expression of integrin α4β1, and infiltration of activated T cells into the spinal cord, without affecting regulatory T cell function. Importantly, expression of β-catenin in mature naive T cells was sufficient to drive integrin α4β1 expression and CNS migration, whereas pharmacologic inhibition of integrin α4β1 reduced the abnormal T cell presence in the CNS of β-catenin-expressing mice. Together, these results implicate deregulation of the Wnt/β-catenin pathway in CNS inflammation and suggest novel therapeutic strategies for neuroinflammatory disorders.

Central European Institute of Technology Masaryk University Brno 625 00 Czech Republic; and

Consiglio Nazionale delle Ricerche Istituto di Biologia Cellulare e Neurobiologia Monterotondo 00015 Italy

Department of Medicine University of Perugia Perugia 06132 Italy

Department of Medicine University of Perugia Perugia 06132 Italy;

Istituto di Ricovero e Cura a Carattere Scientifico Centro Neurolesi Bonino Pulejo Messina 98124 Italy

Mouse Biology Unit European Molecular Biology Laboratory Monterotondo 00015 Italy

Pirogov Russian National Research Medical University 117997 Moscow Russia

Shemyakin Ovchinnikov Institute of Bioorganic Chemistry Russian Academy of Science 117997 Moscow Russia

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