Protection from EAE in DOCK8 mutant mice occurs despite increased Th17 cell frequencies in the periphery

Alicia S. Wilson, Hsei Di Law, Christiane B. Knobbe-Thomsen, Conor J. Kearney, Jane Oliaro, Carole Binsfeld, Gaetan Burgio, Lora Starrs, Dirk Brenner, Katrina L. Randall, Anne Brüstle*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

2 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)770-781
Number of pages12
JournalEuropean Journal of Immunology
Volume49
Issue number5
DOIs
Publication statusPublished - May 2019

Keywords

  • CD4 T cells
  • Th17 cells
  • dedicator of Cytokinesis 8
  • experimental autoimmune encephalomyelitis
  • migration

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