That familiar itch after a mosquito bite is an annoyance but imagine the frustration of those with atopic dermatitis (AD) whose relentless skin irritation is caused by their own immune system turning against them. Overactive T cells with off-balance signalling trigger inflammation, resulting in a cycle of persistent dryness and severe itch.
Studies indicate that AD, or eczema, is driven by complex immune responses, which vary among patients and are influenced by different genetic and molecular factors. “Such heterogeneity suggests there is no ‘one-size-fits-all’ treatment approach, and a precision medicine strategy targeting the molecular basis of each AD subtype should be used to manage the disease,” said Kong-Peng Lam, Executive Director at the Singapore Immunology Network (SIgN).
Building on earlier studies linking mutations in CARD11—a scaffold protein crucial for T cell activation—to severe AD, Lam and colleagues proposed that a docking protein called DOK3 may play a role in modulating immune signalling in AD patients.
In collaboration with researchers from the Bioinformatics Institute (BII), the team explored how DOK3 and CARD11 interact in T cells using techniques like co-immunoprecipitation and computational modelling.
They also conducted functional studies to examine how the absence of DOK3 affects CARD11 signalling and AD symptoms in both human T cells and mice. Finally, they analysed DOK3 expression in T cells from AD patients to see how it correlates with the disease.
The team made three key findings: First, DOK3 interacts with CARD11 to reduce T cell activation by recruiting the phosphatase PP4C, which deactivates CARD11. Second, when DOK3 was removed in mice, it led to increased production of the immune molecule IFN-γ by T cells, providing protection against skin inflammation similar to AD. Finally, higher levels of DOK3 were found in T cells from AD patients and were linked to lower levels of IFN-γ, suggesting that targeting DOK3 could be a promising approach for developing effective, personalised treatments for AD.
“By inhibiting the CARD11-Dok3 interaction and strengthening T cell signalling, we can skew the T cell immune response and promote secretion of IFN-γ, which is protective against AD development,” explained Lam.
The study sheds light on the regulatory mechanisms of T cell signalling, particularly how DOK3 keeps CARD11 inactive. Moving forward, Lam’s team has identified the interacting domains of DOK3 and CARD11 to help design CARD11-based peptides. They are now assessing the therapeutic potential of these peptides in reducing AD severity, with the aim of developing a topical treatment.
The A*STAR-affiliated researchers contributing to this research are from the Singapore Immunology Network (SIgN) and Bioinformatics Institute (BII).
