Regulatory T-cell dysfunction and cutaneous exposure to Staphylococcus aureus underlie eczema in DOCK8 deficiency

Background

Dedicator of cytokinesis 8 (DOCK8)-deficient patients have severe eczema, elevated IgE, and eosinophilia, features of atopic dermatitis (AD).

Objective

We sought to understand the mechanisms of eczema in DOCK8 deficiency.

Methods

Skin biopsy samples were characterized by histology, immunofluorescence microscopy, and gene expression. Skin barrier function was measured by transepidermal water loss. Allergic skin inflammation was elicited in mice by epicutaneous sensitization with ovalbumin (OVA) or cutaneous application of Staphylococcus aureus.

Results

Skin lesions of DOCK8-deficient patients exhibited type 2 inflammation, and the patients' skin was colonized by S aureus, as in AD. Unlike in AD, DOCK8-deficient patients had a reduced FOXP3:CD4 ratio in their skin lesions, and their skin barrier function was intrinsically intact. Dock8^−/− mice exhibited reduced numbers of cutaneous T regulatory (Treg) cells and a normal skin barrier. Dock8^−/− and mice with an inducible Dock8 deletion in Treg cells exhibited increased allergic skin inflammation after epicutaneous sensitization with OVA. DOCK8 was shown to be important for Treg cell stability at sites of allergic inflammation and for the generation, survival, and suppressive activity of inducible Treg cells. Adoptive transfer of wild-type, but not DOCK8-deficient, OVA-specific, inducible Treg cells suppressed allergic inflammation in OVA-sensitized skin of Dock8^−/− mice. These mice developed severe allergic skin inflammation and elevated serum IgE levels after topical exposure to S aureus. Both were attenuated after adoptive transfer of WT but not DOCK8-deficient Treg cells.

Conclusion

Treg cell dysfunction increases susceptibility to allergic skin inflammation in DOCK8 deficiency and synergizes with cutaneous exposure to S aureus to drive eczema in DOCK8 deficiency.