# Role of Dock8 in Mucosal Immunity

> **NIH NIH R01** · SEATTLE CHILDREN'S HOSPITAL · 2022 · $288,272

## Abstract

PROJECT SUMMARY
DOCK8 deficiency in humans leads to severe immunodeficiency. The clinical manifestations of DOCK8
immunodeficiency include recurrent infections, allergies, and malignancies. DOCK8 -deficient patients suffer
from recurrent bacterial infections such as Staphylococcus aureus and fungal infections of the mouth or skin
with Candida, which are suggestive of TH17 cell dysfunction. Although it has been suggested that DOCK8
might coordinate cytoskeletal arrangement, cellular detachment and regulate cell migration, the precise role of
DOCK proteins in the cell remains for the most part unknown. We have recently reported that DOCK8 is
essential for the protective immunity against C. rodentium. DOCK8-deficient mice succumb rapidly to C.
rodentium infection. DOCK8-deficient mice have very low numbers of IL-22-producing RORγt+ ILCs in
comparison to WT mice. DOCK8-deficient RORγt+ ILCs are defective in IL-7-mediated signaling, more prone to
apoptosis and produce less IL-22 than WT mice. We have also found that the generation of TH17 cells during
C. rodentium infection is selectively impaired, whereas the generation of TH1 cells is dramatically increased in
DOCK8-deficient mice in comparison to WT mice. DOCK8 is a very large protein that has been shown to
function as guanine nucleotide exchange factors (GEFs) that binds and activates small GTPases of the
Rho/Rac/Cdc42 family. In order to determine whether DOCK8 function in the generation of TH17 cells is
dependent on its GEF activity for CDC42, or its interaction with WASp, a protein that plays an important role in
the organization and function of the actin cytoskeleton, we infected mice in which CDC42 or WAS was
specifically eliminated in T cells. Whereas DOCK8-deficient mice were unable to mount a robust TH17 cell
response upon infection, CDC42 T cell-deficient or WAS T cell-deficient mice developed a TH17 cell response
as robust as WT mice. From this study, we concluded that at least for the development of TH17 cells, DOCK8
is likely acting as a scaffolding protein rather than a GEF for CDC42, or via its interaction with WASp. Thus, It
is possible that DOCK8 might act as a scaffolding protein that is important for the activation of unknown factors
necessary for the differentiation of TH17 cells. Here we hypothesize that DOCK8 regulates the function of
TH17 cells by interacting with a specific set of proteins selectively expressed in TH17 cells and not in TH1
cells. In order to identify proteins that interact with DOCK8 in vivo, we have generated a novel Knockin mouse
in which endogenous DOCK8 was fused to AVI tag, Flag and GFP reporter. The AVI tag technology will allow
us to perform proteomics and Mass spectrometry analysis in a relatively small number of primary T cells,
whereas the GFP will allow us to perform confocal microscopy and track DOCK8 subcellular localization in
both ILCs and TH17 cells. Overall, our proposed studies will help us understand why DOCK8 deficiency has
such a profoun...

## Key facts

- **NIH application ID:** 10440281
- **Project number:** 5R01AI140626-05
- **Recipient organization:** SEATTLE CHILDREN'S HOSPITAL
- **Principal Investigator:** Richard Goff James
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $288,272
- **Award type:** 5
- **Project period:** 2018-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10440281

## Citation

> US National Institutes of Health, RePORTER application 10440281, Role of Dock8 in Mucosal Immunity (5R01AI140626-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10440281. Licensed CC0.

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