Wnt/β-Catenin Signaling Induces Integrin α4β1 in T Cells and Promotes a Progressive Neuroinflammatory Disease in Mice

• Published in: The Journal of immunology (1950) 2017-11, Vol.199 (9), p.3031-3041
• Main Authors: Sorcini, Daniele, Bruscoli, Stefano, Frammartino, Tiziana, Cimino, Monica, Mazzon, Emanuela, Galuppo, Maria, Bramanti, Placido, Al-Banchaabouchi, Mumna, Farley, Dominika, Ermakova, Olga, Britanova, Olga, Izraelson, Mark, Chudakov, Dmitry, Biagioli, Michele, Sportoletti, Paolo, Flamini, Sara, Raspa, Marcello, Scavizzi, Ferdinando, Nerlov, Claus, Migliorati, Graziella, Riccardi, Carlo, Bereshchenko, Oxana
• Format: Article
• Language: English
• Subjects: Animals; beta Catenin - genetics; beta Catenin - immunology; CD4 antigen; Cell activation; Central nervous system; Deregulation; Inflammation - genetics; Inflammation - immunology; Inflammation - pathology; Inflammatory diseases; Integrin alpha4beta1 - genetics; Integrin alpha4beta1 - immunology; Lymphocytes; Lymphocytes T; Mice; Mice, Knockout; Spinal cord; Spinal Cord - immunology; Spinal Cord - pathology; Spinal Cord Diseases - genetics; Spinal Cord Diseases - immunology; Spinal Cord Diseases - pathology; Th1 Cells - immunology; Th1 Cells - pathology; Wnt protein; Wnt Signaling Pathway - genetics; Wnt Signaling Pathway - immunology; β-Catenin
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1700247

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.