RT Journal Article
SR Electronic
T1 Itk Signals Promote Neuroinflammation by Regulating CD4<sup>+</sup> T-Cell Activation and Trafficking
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 221
OP 233
DO 10.1523/JNEUROSCI.1957-14.2015
VO 35
IS 1
A1 Arun K. Kannan
A1 Do-Geun Kim
A1 Avery August
A1 Margaret S. Bynoe
YR 2015
UL http://www.jneurosci.org/content/35/1/221.abstract
AB Here we demonstrate that interleukin-2-inducible T-cell kinase (Itk) signaling in cluster of differentiation 4-positive (CD4+) T cells promotes experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS). We show that Itk−/− mice exhibit reduced disease severity, and transfer of Itk−/− CD4+ T cells into T cell-deficient recipients results in lower disease severity. We observed a significant reduction of CD4+ T cells in the CNS of Itk−/− mice or recipients of Itk−/− CD4+ T cells during EAE, which is consistent with attenuated disease. Itk−/− CD4+ T cells exhibit defective response to myelin antigen stimulation attributable to displacement of filamentous actin from the CD4+ coreceptor. This results in inadequate transmigration of Itk−/− CD4+ T cells into the CNS and across brain endothelial barriers in vitro. Finally, Itk−/− CD4+ T cells show significant reduction in production of T-helper 1 (Th1) and Th17 cytokines and exhibit skewed T effector/T regulatory cell ratios. These results indicate that signaling by Itk promotes autoimmunity and CNS inflammation, suggesting that it may be a viable target for treatment of MS.