ILC3 deficiency and generalized ILC abnormalities in DOCK8-deficient patients

Area of Science:

• Immunology
• Cell Biology
• Genetics

Background:

• Dedicator of cytokinesis 8 (DOCK8) deficiency is a primary cause of autosomal recessive hyper-IgE syndrome (HIES).
• Previous studies indicated a loss of group 3 innate lymphoid cells (ILCs) in a DOCK8-deficient mouse model.
• This study investigates the role of DOCK8 in human ILC subset function and maintenance.

Purpose of the Study:

• To determine if DOCK8 is essential for the function and survival of human ILC subsets.
• To compare ILC subsets in DOCK8-deficient patients with those in patients with STAT3 mutations and healthy controls.

Main Methods:

• Flow cytometry and real-time qPCR were used to analyze peripheral blood ILC subsets (ILC1-3) from DOCK8-deficient patients, AD-HIES patients, and healthy controls.
• Sorted ILCs were cultured to assess survival, apoptosis, proliferation, and activation in response to key cytokines (IL-7, IL-12, IL-23).
• Phospho-flow assays were employed to evaluate cytokine signaling pathways.

Main Results:

• DOCK8-deficient patients showed a significant reduction in ILC3s and, to a lesser extent, ILC2s compared to controls and STAT3-mutant patients.
• DOCK8-deficient ILC subsets exhibited impaired proliferation, reduced IL-7 receptor (IL-7R) expression, and diminished responses to IL-7, IL-12, and IL-23.
• These ILCs were also more susceptible to apoptosis.

Conclusions:

• DOCK8 is crucial for the expansion, survival, and cytokine responsiveness of human ILC3s.
• DOCK8 deficiency results in the depletion of ILC3s from peripheral blood.
• The loss of ILC3s in DOCK8-deficient individuals may contribute to their increased susceptibility to infections.