Itk signals promote neuroinflammation by regulating CD4+ T-cell activation and trafficking.

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.