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DOCK8 Expression in Regulatory T Cells Maintains their Stability and Limits Contact Hypersensitivity.

Authors
  • Wilkie, Hazel1
  • Janssen, Erin1
  • Leyva-Castillo, Juan Manuel1
  • Geha, Raif S2
  • 1 Division of Immunology, Boston Children's Hospital, Boston, Massachusetts, USA; Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
  • 2 Division of Immunology, Boston Children's Hospital, Boston, Massachusetts, USA; Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA. Electronic address: [email protected]
Type
Published Article
Journal
Journal of Investigative Dermatology
Publisher
Elsevier
Publication Date
Jun 01, 2021
Volume
141
Issue
6
Identifiers
DOI: 10.1016/j.jid.2020.09.027
PMID: 33171169
Source
Medline
Language
English
License
Unknown

Abstract

Chronic dermatitis is a hallmark of Dedicator of cytokinesis 8 (DOCK8) deficiency. The migration of DOCK8-deficient T cells to the skin and their survival there have been reported to be defective. Surprisingly, we found that Dock8-/- mice demonstrated an exaggerated contact hypersensitivity (CHS) response to oxazolone with increased ear swelling, T-cell infiltration, and expression of Ifng. To understand the mechanisms of persistent skin inflammation in DOCK8 deficiency, we examined mice with selective deficiency of DOCK8 in T cells or T regulatory cells (Tregs) and found that both have exaggerated CHS. Moreover, oral tolerance to oxazolone, mediated by Tregs, was impaired in Dock8-/- mice. Transfer of Tregs from oxazolone-sensitized wild-type mice, but not Dock8-/- mice, reduced the CHS response of Dock8-/- recipients. Lack of DOCK8 in Tregs resulted in their acquisition of a pathogenic FOXP3+T-bet+IFNγ+ phenotype at CHS sites and promoted their conversion into ex-Tregs. The transfer of Tregs from Dock8-/- mice increased the CHS response of wild-type recipients to oxazolone. Thus, DOCK8 expression in Tregs limits CHS by promoting Treg stability and fitness in inflamed skin. Interventions aimed at ameliorating Treg function may be useful in treating skin inflammation in DOCK8 deficiency. Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

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