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

Upon antigen recognition, T cells undergo rapid cell proliferation and differentiation, which is accompanied by a drastic change in cellular metabolism. The ADP-ribosylation factor (Arf) pathway contributes to cellular homeostasis by orchestrating vesicle trafficking, and our previous study using mice lacking both Arf1 and Arf6 (Arf-KO) revealed that Th17-mediated autoimmune diseases were markedly suppressed in Arf-KO mice though the precise mechanism remained elusive. Here, we show that the Arf pathway modulates cellular metabolism in T-cell activation and survival. We found that the lack of Arf1 and Arf6 resulted in hyper-activation of mTOR complex 1 (mTORC1), a master regulator of cellular metabolism, as well as unresolved endoplasmic reticulum (ER) stress, leading to exaggerated apoptosis during T-cell activation. We further demonstrated that treatment with IL-21, a potent inducer of Tfh differentiation, rescued Arf-KO T cells from apoptosis by attenuating ER stress in vitro. Accordingly, antigen-specific antibody production and host defenses against infections such as Leishmania major or Heligmosomoides polygyrus infections were significantly preserved in Arf-KO mice. Taken together, these findings provide mechanistic insights linking the Arf pathway with T-cell homeostasis during activation and identify the Arf pathway as an ideal therapeutic target for autoimmune diseases with a low risk of opportunistic infections.