Background/Purpose: DOCK8 deficiency leads to autosomal recessive Hyper-IgE syndrome (AR-HIES). DOCK8 deficient patients develop recurrent sinopulmonary infections, chronic mucocutaneous viral infections, hyper-IgE, eosinophilia, food allergies, and severe dermatitis [1, 2]. We previously reported that the number and in vitro suppressive function of circulating regulatory T (Treg) cells are significantly reduced in DOCK8 deficient patients [3]. Paradoxically, they seldom develop autoimmunity, we propose that this is due to their impaired T effector (Teff) cell function.

Methods: We generated and analyzed Dock8^-/- mice and mice with a selective DOCK8 deficiency in their Treg cells. Treg cell markers and in vitro suppressive function were investigated using flow cytometry. STAT5 phosphorylation was measured by flow cytometry and confocal microscopy. Using co-immunoprecipitation experiments, we examined the association between DOCK8 and STAT5.

Results: We determined that Dock8^-/- mice have decreased Treg numbers and impaired in vitro function of Treg cells, but do not develop autoimmunity. In contrast, mice with selective DOCK8 deficiency in their Treg cells spontaneously develop lymphoproliferation, autoantibodies, and severe gastrointestinal inflammation, despite normal percentages of Treg cells. We found that DOCK8 associates with STAT5 and plays crucial role in IL-2 driven STAT5 phosphorylation and nuclear translocation in Treg cells. These findings indicate that DOCK8 expression in Treg cells plays a critical role in self-tolerance by enhancing IL-2 driven STAT5 signaling, which is essential for Treg cell function, and suggest that deficient Teff cell function might protect DOCK8 deficient patients from autoimmunity.

Conclusion: These findings suggest that DOCK8 expression in Treg cells plays a critical role in self-tolerance by enhancing IL-2 driven STAT5 signaling. Furthermore, our data support the hypothesis that deficient Teff cell function may protect DOCK8 deficient patients from autoimmunity. References:

1. Engelhardt, K.R., et al., Large deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndrome.J Allergy Clin Immunol, 2009. 124(6): p. 1289-302 e4.

2. Zhang, Q., et al., Combined immunodeficiency associated with DOCK8 mutations.The New England journal of medicine, 2009. 361(21): p. 2046-55.

3. Janssen, E., et al., Dedicator of cytokinesis 8-deficient patients have a breakdown in peripheral B-cell tolerance and defective regulatory T cells. The Journal of allergy and clinical immunology, 2014.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/dock8-associates-with-stat5-and-promotes-regulatory-t-cell-function/