@article{8e1eaf551296462cb03bc49660b2a441,
title = "Protection from EAE in DOCK8 mutant mice occurs despite increased Th17 cell frequencies in the periphery",
abstract = "Mutation of Dedicator of cytokinesis 8 (DOCK8) has previously been reported to provide resistance to the Th17 cell dependent EAE in mice. Contrary to expectation, we observed an elevation of Th17 cells in two different DOCK8 mutant mouse strains in the steady state. This was specific for Th17 cells with no change in Th1 or Th2 cell populations. In vitro Th cell differentiation assays revealed that the elevated Th17 cell population was not due to a T cell intrinsic differentiation bias. Challenging these mutant mice in the EAE model, we confirmed a resistance to this autoimmune disease with Th17 cells remaining elevated systemically while cellular infiltration in the CNS was reduced. Infiltrating T cells lost the bias toward Th17 cells indicating a relative reduction of Th17 cells in the CNS and a Th17 cell specific migration disadvantage. Adoptive transfers of Th1 and Th17 cells in EAE-affected mice further supported the Th17 cell-specific migration defect, however, DOCK8-deficient Th17 cells expressed normal Th17 cell-specific CCR6 levels and migrated toward chemokine gradients in transwell assays. This study shows that resistance to EAE in DOCK8 mutant mice is achieved despite a systemic Th17 bias.",
keywords = "CD4 T cells, Th17 cells, dedicator of Cytokinesis 8, experimental autoimmune encephalomyelitis, migration",
author = "Wilson, {Alicia S.} and Law, {Hsei Di} and Knobbe-Thomsen, {Christiane B.} and Kearney, {Conor J.} and Jane Oliaro and Carole Binsfeld and Gaetan Burgio and Lora Starrs and Dirk Brenner and Randall, {Katrina L.} and Anne Br{\"u}stle",
note = "Funding Information: Acknowledgements: A.S.W., K.L.R., and A.B. designed and analyzed the experiments and wrote the manuscript. A.S.W., H.D.L., C.B.K.T., C.J.K., J.O., C.B., G.B., L.S., and D.B. performed and analyzed experiments. This work was supported by an Australian Government Research Training Program Scholarship (A.S.W.), NHMRC project grants 1022922 (K.L.R.) and 1079318 (J.O., K.L.R.), ACT Health Private Practice Fund Major Grant 2015 and 2016 (K.L.R). C.B.K.T. was supported by the DKH (110663) and the BMBF (01ZX1401B). D.B. is funded through the FNR-ATTRACT program (A14/BM/7632103) and an FNR-CORE grant (C15/BM/10355103) of the Luxembourg National Research Fund. The authors thank all members of the Br{\"u}stle laboratory, past and present, for their support and the flow cytometry facility at The John Curtin School of Medical Research for their excellent services. The authors further thank Dr. Emmalene Bartlett for her insightful scientific editing. Funding Information: A.S.W., K.L.R., and A.B. designed and analyzed the experiments and wrote the manuscript. A.S.W., H.D.L., C.B.K.T., C.J.K., J.O., C.B., G.B., L.S., and D.B. performed and analyzed experiments. This work was supported by an Australian Government Research Training Program Scholarship (A.S.W.), NHMRC project grants 1022922 (K.L.R.) and 1079318 (J.O., K.L.R.), ACT Health Private Practice Fund Major Grant 2015 and 2016 (K.L.R). C.B.K.T. was supported by the DKH (110663) and the BMBF (01ZX1401B). D.B. is funded through the FNR-ATTRACT program (A14/BM/7632103) and an FNR-CORE grant (C15/BM/10355103) of the Luxembourg National Research Fund. The authors thank all members of the Br?stle laboratory, past and present, for their support and the flow cytometry facility at The John Curtin School of Medical Research for their excellent services. The authors further thank Dr. Emmalene Bartlett for her insightful scientific editing. Publisher Copyright: {\textcopyright} 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim",
year = "2019",
month = may,
doi = "10.1002/eji.201847960",
language = "English",
volume = "49",
pages = "770--781",
journal = "European Journal of Immunology",
issn = "0014-2980",
publisher = "Wiley-VCH Verlag",
number = "5",
}