IL-21 Rescues the Defect of IL-10-Producing Regulatory B Cells and Improves Allergic Asthma in DOCK8 Deficient Mice

Front Immunol. 2021 Nov 15;12:695596. doi: 10.3389/fimmu.2021.695596. eCollection 2021.

Abstract

Mutations in human DOCK8 cause a combined immunodeficiency syndrome characterized by allergic diseases such as asthma and food allergy. However, the underlying mechanism is unclear. Regulatory B (Breg) cells that produce IL-10 exert potent immunosuppressive functions in patients with allergic and autoimmune disorders. DOCK8-deficient B cells show diminished responses to TLR9 signaling, suggesting a possible defect in IL-10-producing Breg cells in those with DOCK8 deficiency, which may contribute to allergies. Here, we isolated peripheral blood mononuclear cells from DOCK8-deficient patients and generated a Dock8 KO mouse model to study the effect of DOCK8 deficiency on Breg cells. DOCK8-deficient patients and Dock8 KO mice harbored quantitative and qualitative defects in IL-10-producing Breg cells; these defects were caused by abnormal Dock8-/- CD4+ T cells. We found that recombinant murine (rm)IL-21 restored the function of Bregs both in vitro and in Dock8 KO mice, leading to reduced inflammatory cell infiltration of the lungs in a murine asthma model. Overall, the results provide new insight into the potential design of Breg-based or IL-21-based therapeutic strategies for allergic diseases, including asthma associated with DOCK8 deficiency.

Keywords: DOCK8 deficiency; IL-10; IL-21; asthma; regulatory B cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Animals
  • Asthma / immunology*
  • Asthma / therapy*
  • B-Lymphocytes, Regulatory / immunology*
  • B-Lymphocytes, Regulatory / metabolism
  • CD4-Positive T-Lymphocytes / immunology
  • Case-Control Studies
  • Child
  • Child, Preschool
  • Disease Models, Animal
  • Female
  • Guanine Nucleotide Exchange Factors / deficiency*
  • Guanine Nucleotide Exchange Factors / genetics
  • Guanine Nucleotide Exchange Factors / immunology
  • Humans
  • In Vitro Techniques
  • Interleukin-10 / biosynthesis*
  • Interleukins / immunology
  • Interleukins / therapeutic use*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutation
  • Phosphorylation
  • Recombinant Proteins / immunology
  • Recombinant Proteins / therapeutic use
  • STAT3 Transcription Factor / metabolism

Substances

  • DOCK8 protein, human
  • Dock8 protein, mouse
  • Guanine Nucleotide Exchange Factors
  • IL10 protein, mouse
  • Interleukins
  • Recombinant Proteins
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Interleukin-10
  • interleukin-21