Wnt/Beta-Catenin Signaling Induces Integrin Alpha 4 Beta 1 In T Cells And Promotes A Progressive Neuroinflammatory Disease In Mice

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 beta-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 beta-catenin expression in T cells leads to aberrant and Th1-biased T cell activation, enhanced expression of integrin alpha 4 beta 1, and infiltration of activated T cells into the spinal cord, without affecting regulatory T cell function. Importantly, expression of beta-catenin in mature naive T cells was sufficient to drive integrin alpha 4 beta 1 expression and CNS migration, whereas pharmacologic inhibition of integrin alpha 4 beta 1 reduced the abnormal T cell presence in the CNS of beta-catenin-expressing mice. Together, these results implicate deregulation of the Wnt/beta-catenin pathway in CNS inflammation and suggest novel therapeutic strategies for neuroinflammatory disorders.