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タイトル: | Nonoverlapping roles of PD-1 and FoxP3 in maintaining immune tolerance in a novel autoimmune pancreatitis mouse model. |
著者: | Zhang, Baihao Chikuma, Shunsuke Hori, Shohei Fagarasan, Sidonia Honjo, Tasuku ![]() ![]() |
著者名の別形: | 章, 白浩 竹馬, 俊介 本庶, 佑 |
キーワード: | immune tolerance autoimmunity T lymphocytes regulatory T cell PD-1 |
発行日: | 7-Jul-2016 |
出版者: | National Academy of Sciences |
誌名: | Proceedings of the National Academy of Sciences of the United States of America |
巻: | 113 |
号: | 30 |
開始ページ: | 8490 |
終了ページ: | 8495 |
抄録: | PD-1 (programmed-death 1), an immune-inhibitory receptor required for immune self-tolerance whose deficiency causes autoimmunity with variable severity and tissue specificity depending on other genetic factors, is expressed on activated T cells, including the transcription factor FoxP3(+) Treg cells known to play critical roles in maintaining immune tolerance. However, whether PD-1 expression by the Treg cells is required for their immune regulatory function, especially in autoimmune settings, is still unclear. We found that mice with partial FoxP3 insufficiency developed early-onset lympho-proliferation and lethal autoimmune pancreatitis only when PD-1 is absent. The autoimmune phenotype was rescued by the transfer of FoxP3-sufficient T cells, regardless of whether they were derived from WT or PD-1-deficient mice, indicating that Treg cells dominantly protect against development of spontaneous autoimmunity without intrinsic expression of PD-1. The absence of PD-1 combined with partial FoxP3 insufficiency, however, led to generation of ex-FoxP3 T cells with proinflammatory properties and expansion of effector/memory T cells that contributed to the autoimmune destruction of target tissues. Altogether, the results suggest that PD-1 and FoxP3 work collaboratively in maintaining immune tolerance mostly through nonoverlapping pathways. Thus, PD-1 is modulating the activation threshold and maintaining the balance between regulatory and effector T cells, whereas FoxP3 is sufficient for dominant regulation through maintaining the integrity of the Treg function. We suggest that genetic or environmental factors that even moderately affect the expression of both PD-1 and FoxP3 can cause life-threatening autoimmune diseases by disrupting the T-cell homeostasis. |
記述: | 免疫のブレーキPD-1は、制御性T細胞との役割分担によって自己免疫性膵炎を抑制する. 京都大学プレスリリース. 2016-07-20. |
著作権等: | The final version of record is available at http://www.pnas.org/content/early/2016/07/06/1608873113. この論文は出版社版でありません。引用の際には出版社版をご確認ご利用ください。 This is not the published version. Please cite only the published version. |
URI: | http://hdl.handle.net/2433/216040 |
DOI(出版社版): | 10.1073/pnas.1608873113 |
PubMed ID: | 27410049 |
関連リンク: | https://www.kyoto-u.ac.jp/ja/research-news/2016-07-20 |
出現コレクション: | 学術雑誌掲載論文等 |
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