Autoimmune disease risk gene ANKRD55 promotes TH17 effector function through metabolic modulation.

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• Genome-wide association studies link the ankyrin repeat domain 55 (ANKRD55) gene locus to autoimmune diseases.
• The precise biological function and inflammatory role of ANKRD55 remain largely uncharacterized.

Purpose of the Study:

• To elucidate the function of ANKRD55 in T cell-mediated immunity and inflammation.
• To investigate the molecular mechanisms underlying ANKRD55's role in T helper 17 (TH17) cell responses.

Main Methods:

• Utilized Ankrd55-deficient mouse models to study T cell-mediated colitis and bacterial infection susceptibility.
• Performed mechanistic studies involving CD4+ T cell proliferation, cytokine production, mitochondrial respiration, and LKB1 pathway activation.
• Investigated the impact of LKB1 deletion on IL-17 production in Ankrd55-deficient T cells.

Main Results:

• Ankrd55 deficiency conferred protection against T cell-mediated colitis but increased susceptibility to Citrobacter rodentium infection.
• ANKRD55 deletion intrinsically impaired CD4+ T cell proliferation and reduced TH17 effector cytokine production.
• Loss of ANKRD55 was associated with impaired mitochondrial respiration and activation of the LKB1 pathway, which could rescue IL-17 production.

Conclusions:

• ANKRD55 functions as a critical modulator of T cell metabolism, specifically impacting TH17 cell responses.
• The findings highlight ANKRD55 as a potential therapeutic target for various autoimmune diseases.