title: Itk signals promote neuroinflammation by regulating CD4+ T-cell activation and trafficking.
abstract: 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.
authors.affiliation: Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853.
authors.forename: Arun K
authors.initials: AK
authors.lastname: Kannan
authors.affiliation: Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853.
authors.forename: Do-Geun
authors.initials: DG
authors.lastname: Kim
authors.affiliation: Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853 msb76@cornell.edu averyaugust@cornell.edu.
authors.forename: Avery
authors.identifier: http://orcid.org/0000-0003-4968-3415
authors.initials: A
authors.lastname: August
authors.affiliation: Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853 msb76@cornell.edu averyaugust@cornell.edu.
authors.forename: Margaret S
authors.initials: MS
authors.lastname: Bynoe
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D002465:Cell Movement / Q000502:physiology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism* / Q000473:pathology; D005260:Female; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D021381:Protein Transport / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D011505:Protein-Tyrosine Kinases; C080813:emt protein-tyrosine kinase
keywords: Th17; Treg; autoimmune encephalomyelitis; migration; multiple sclerosis