The Arf pathway is required for resolving endoplasmic reticulum stress during T-cell activation

Area of Science:

• Immunology
• Cellular Metabolism
• Molecular Biology

Background:

• T cells require metabolic changes for activation and differentiation.
• The ADP-ribosylation factor (Arf) pathway regulates vesicle trafficking and cellular homeostasis.
• Previous studies showed Arf1 and Arf6 deficiency suppresses Th17-mediated autoimmune diseases.

Purpose of the Study:

• To elucidate the mechanism by which the Arf pathway influences T-cell activation, metabolism, and survival.
• To investigate the role of Arf1 and Arf6 in T-cell homeostasis.
• To identify the Arf pathway as a potential therapeutic target for autoimmune disorders.

Main Methods:

• Utilized Arf1 and Arf6 knockout (Arf-KO) mice.
• Analyzed T-cell activation, proliferation, and apoptosis.
• Assessed mTOR complex 1 (mTORC1) activity and endoplasmic reticulum (ER) stress.
• Investigated the effect of IL-21 treatment on Arf-KO T cells.
• Evaluated host defense mechanisms against Leishmania major and Heligmosomoides polygyrus infections.

Main Results:

• Arf-KO T cells exhibited hyper-activated mTORC1 and unresolved ER stress, leading to increased apoptosis during activation.
• IL-21 treatment rescued Arf-KO T cells by attenuating ER stress.
• Arf-KO mice showed preserved antibody production and enhanced resistance to Leishmania major and Heligmosomoides polygyrus infections.
• Arf pathway deficiency suppressed Th17-mediated autoimmune diseases.

Conclusions:

• The Arf pathway is a critical regulator of T-cell metabolism and survival during activation.
• Dysregulation of the Arf pathway leads to metabolic and ER stress imbalances in T cells.
• Targeting the Arf pathway offers a promising therapeutic strategy for autoimmune diseases with a reduced risk of opportunistic infections.