論文種別	原著(症例報告除く)
言語種別	英語
査読の有無	その他(不明)
表題	The Arf pathway is required for resolving ER stress during T cell activation.
掲載誌名	正式名：International immunology 略　 称：Int Immunol ISSNコード：14602377/09538178
掲載区分	国外
巻・号・頁	pp.Online ahead of print
著者・共著者	Mami Sumiyoshi, Yui Kotani, Chikako Shimokawa, Sukhonthip Khueangchiangkhwang, Yoichi Maekawa, Yoshiyuki Matsuo, Yoshiki Yasukochi, Koichiro Higasa, Yasunori Kanaho, Toshio Watanabe, Satoshi Matsuda
発行年月	2025/05
概要	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 its precise mechanism remained elusive. Here, we show that 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 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 cells homeostasis during activation and identify the Arf pathway as an ideal therapeutic target for autoimmune diseases with a low risk of opportunistic infections.
DOI	10.1093/intimm/dxaf028
PMID	40405457