Development of central nervous system autoimmunity is impaired in the absence of wiskott-aldrich syndrome protein

Abstract

Wiskott-Aldrich Syndrome protein (WASP) is a key regulator of the actin cytoskeleton in hematopoietic cells. Defective expression of WASP leads to multiple abnormalities in different hematopoietic cells. Despite severe impairment of T cell function, WAS patients exhibit a high prevalence of autoimmune disorders. We attempted to induce EAE, an animal model of organ-specific autoimmunity affecting the CNS that mimics human MS, in Was -/- mice. We describe here that Was-/- mice are markedly resistant against EAE, showing lower incidence and milder score, reduced CNS inflammation and demyelination as compared to WT mice. Microglia was only poorly activated in Was-/- mice. Antigen-induced T-cell proliferation, Th-1 and -17 cytokine production and integrin-dependent adhesion were increased in Was-/- mice. However, adoptive transfer of MOG-activated T cells from Was-/- mice in WT mice failed to induce EAE. Was-/- mice were resistant against EAE also when induced by adoptive transfer of MOG-activated T cells from WT mice. Was+/- heterozygous mice developed an intermediate clinical phenotype between WT and Was-/- mice, and they displayed a mixed population of WASP-positive and -negative T cells in the periphery but not in their CNS parenchyma, where the large majority of inflammatory cells expressed WASP. In conclusion, in absence of WASP, T-cell responses against a CNS autoantigen are increased, but the ability of autoreactive T cells to induce CNS autoimmunity is impaired, most probably because of an inefficient T-cell transmigration into the CNS and defective CNS resident microglial function. © 2014 Bosticardo et al.