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JCI Insight. 2017 Oct 5;2(19). pii: 94298. doi: 10.1172/jci.insight.94298. [Epub ahead of print]

DOCK8 enforces immunological tolerance by promoting IL-2 signaling and immune synapse formation in Tregs.

Author information

1
Division of Immunology, Boston Children's Hospital, Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
2
Department of Bioengineering and Koch Institute of Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
3
Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
4
Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, Massachusetts, USA; Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
5
Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.

Abstract

Patients deficient in the guanine nucleotide exchange factor DOCK8 have decreased numbers and impaired in vitro function of Tregs and make autoantibodies, but they seldom develop autoimmunity. We show that, similarly, Dock8-/- mice have decreased numbers and impaired in vitro function of Tregs but do not develop autoimmunity. In contrast, mice with selective DOCK8 deficiency in Tregs develop lymphoproliferation, autoantibodies, and gastrointestinal inflammation, despite a normal percentage and in vitro function of Tregs, suggesting that deficient T effector cell function might protect DOCK8-deficient patients from autoimmunity. We demonstrate that DOCK8 associates with STAT5 and is important for IL-2-driven STAT5 phosphorylation in Tregs. DOCK8 localizes within the lamellar actin ring of the Treg immune synapse (IS). Dock8-/- Tregs have abnormal TCR-driven actin dynamics, decreased adhesiveness, an altered gene expression profile, an unstable IS with decreased recruitment of signaling molecules, and impaired transendocytosis of the costimulatory molecule CD86. These data suggest that DOCK8 enforces immunological tolerance by promoting IL-2 signaling, TCR-driven actin dynamics, and the IS in Tregs.

PMID:
28978806
DOI:
10.1172/jci.insight.94298
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