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.
Highlights
Specialty section: This article was submitted to Primary Immunodeficiencies, a section of the journal Frontiers in Immunology
Patients with hyper-IgE syndromes (HIES) caused by dedicator of cytokinesis 8 (DOCK8) deficiency are more susceptible to developing allergic diseases than those with HIES caused by STAT3 mutations [2]
We found that the percentage and number of CD19+CD24hiCD27+ memory B cells within the Peripheral blood mononuclear cells (PBMCs) population was lower in patients than in age-matched healthy controls (HCs) (Figure 1A), whereas the total B cell (Figure 1B) and CD19+CD24hiCD38hi immature transitional B cell populations (Figure 1C), which harbor IL-10-producing Breg cells, were normal
Summary
All patients were admitted to the Children’s Hospital of Chongqing Medical University. C57BL/6 mice were purchased from the Laboratory Animal Center, Chongqing Medical University. Mononuclear cells isolated from the spleen of DOCK8 KO and WT mice were stained with the following antibodies: antiCD19 FITC, anti-CD5 PE, and anti-CD1d APC (CD1dhiCD5+ B cells); anti-CD19 FITC, anti-CD23 PE, anti-CD21 APC, and antiCD24 Percp-cy5.5 (T2-MZP cells) (all antibodies were from BioLegend, CA). Mononuclear cells isolated from spleen cells of chimera mice were stained with anti-CD45.1 BV510, CD45.2 FITC, anti-CD19 APC, and anti-IL-10 PE (BioLegend, CA). Mononuclear cells isolated from the spleen of CD4 KO mice were stained with anti-CD19 FITC or APC, anti-CD5 PE, anti-CD1d APC, antiCD23 PE, anti-CD21 APC, anti-CD24 Percp-cy5.5, or anti-IL-10 PE (BioLegend, CA).
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
