OBJECTIVE: To understand the mechanisms of eczema in DOCK8 deficiency.
METHODS: Skin biopsies were characterized for histology, immuno-fluorescence microscopy, and gene expression. Skin barrier function was measured by trans-epidermal water loss. Allergic skin inflammation was elicited in mice by epicutaneous (EC) sensitization with ovalbumin (OVA) or cutaneous application of S. aureus.
RESULTS: Skin lesions of DOCK8-deficient patients exhibited type-2 inflammation and the patients' skin was colonized by S. aureus, like 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 cells (Tregs) and a normal skin barrier. Dock8-/- mice and mice with an inducible Dock8 deletion in Tregs exhibited increased allergic skin inflammation following EC sensitization with OVA. DOCK8 was shown to be important for Treg stability at sites of allergic inflammation and for the generation, survival, and suppressive activity of inducible Tregs (iTregs). Adoptive transfer of wild-type, but not DOCK8-deficient, OVA-specific iTregs suppressed allergic inflammation in OVA-sensitized skin of Dock8-/- mice. These mice developed severe allergic skin inflammation and elevated serum IgE levels following topical exposure to S. aureus. Both were attenuated following adoptive transfer of WT but not DOCK8 deficient Tregs 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.