Thais Boccia, Weikang Pan, Victor Fattori, Rodrigo Cervantes-Diaz, Michael S. Rogers, Ivan Zanoni, Alex G. Cuenca
{"title":"辅助调节通过 NLRP3/IL-1 塑造适应性免疫反应并促进训练有素的免疫耐受性","authors":"Thais Boccia, Weikang Pan, Victor Fattori, Rodrigo Cervantes-Diaz, Michael S. Rogers, Ivan Zanoni, Alex G. Cuenca","doi":"10.1101/2024.09.06.611736","DOIUrl":null,"url":null,"abstract":"Trained immunity enhances responsiveness of the innate immune system upon restimulation. Although adjuvants are used to enhance immune responses, we showed that repeated administration of alum, termed adjuvant conditioning (AC), establishes an immunosuppressive environment that delays allogeneic graft rejection by expanding myeloid-derived suppressor cells (MDSCs). Here, we show that AC-induced MDSCs suppress antigen specific adaptive responses both in vitro and in vivo, and that the immunosuppression is abolished in the absence of NLRP3 and IL-1 signaling. Allogeneic pancreatic islets transplanted into AC-treated NLRP3-/- mice are not protected, demonstrating that AC requires NLRP3 signaling. Finally, AC also has an immunosuppressive effect on human PBMCs. Overall, our data show that AC establishes an immunosuppressive milieu via the NLRP3/IL-1 axis, leading to trained immunosuppression, or trained tolerance. Our findings give a potent mandate to explore the possibility to target the NLRP3/IL-1 pathway as a new promising strategy to condition transplant recipients and promote allograft tolerance.","PeriodicalId":501182,"journal":{"name":"bioRxiv - Immunology","volume":"80 1","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Adjuvant conditioning shapes the adaptive immune response and promotes trained immunotolerance via NLRP3/IL-1\",\"authors\":\"Thais Boccia, Weikang Pan, Victor Fattori, Rodrigo Cervantes-Diaz, Michael S. Rogers, Ivan Zanoni, Alex G. Cuenca\",\"doi\":\"10.1101/2024.09.06.611736\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Trained immunity enhances responsiveness of the innate immune system upon restimulation. Although adjuvants are used to enhance immune responses, we showed that repeated administration of alum, termed adjuvant conditioning (AC), establishes an immunosuppressive environment that delays allogeneic graft rejection by expanding myeloid-derived suppressor cells (MDSCs). Here, we show that AC-induced MDSCs suppress antigen specific adaptive responses both in vitro and in vivo, and that the immunosuppression is abolished in the absence of NLRP3 and IL-1 signaling. Allogeneic pancreatic islets transplanted into AC-treated NLRP3-/- mice are not protected, demonstrating that AC requires NLRP3 signaling. Finally, AC also has an immunosuppressive effect on human PBMCs. Overall, our data show that AC establishes an immunosuppressive milieu via the NLRP3/IL-1 axis, leading to trained immunosuppression, or trained tolerance. Our findings give a potent mandate to explore the possibility to target the NLRP3/IL-1 pathway as a new promising strategy to condition transplant recipients and promote allograft tolerance.\",\"PeriodicalId\":501182,\"journal\":{\"name\":\"bioRxiv - Immunology\",\"volume\":\"80 1\",\"pages\":\"\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2024-09-12\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"bioRxiv - Immunology\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1101/2024.09.06.611736\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"bioRxiv - Immunology","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1101/2024.09.06.611736","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0
摘要
训练免疫可增强先天性免疫系统在再次刺激时的反应能力。虽然佐剂可用于增强免疫反应,但我们发现,反复给予明矾(称为佐剂调节(AC))可建立免疫抑制环境,通过扩大髓源性抑制细胞(MDSCs)来延迟异体移植排斥反应。在这里,我们发现 AC 诱导的 MDSCs 在体外和体内都能抑制抗原特异性适应性反应,而且在缺乏 NLRP3 和 IL-1 信号传导的情况下,这种免疫抑制会消失。异体胰岛移植到经过 AC 处理的 NLRP3-/- 小鼠体内不会受到保护,这表明 AC 需要 NLRP3 信号传导。最后,AC 对人类 PBMCs 也有免疫抑制作用。总之,我们的数据表明,AC 可通过 NLRP3/IL-1 轴建立免疫抑制环境,导致训练有素的免疫抑制或训练有素的耐受。我们的研究结果有力地推动了探索以 NLRP3/IL-1 通路为靶点作为调节移植受者和促进异体移植耐受的新策略的可能性。
Adjuvant conditioning shapes the adaptive immune response and promotes trained immunotolerance via NLRP3/IL-1
Trained immunity enhances responsiveness of the innate immune system upon restimulation. Although adjuvants are used to enhance immune responses, we showed that repeated administration of alum, termed adjuvant conditioning (AC), establishes an immunosuppressive environment that delays allogeneic graft rejection by expanding myeloid-derived suppressor cells (MDSCs). Here, we show that AC-induced MDSCs suppress antigen specific adaptive responses both in vitro and in vivo, and that the immunosuppression is abolished in the absence of NLRP3 and IL-1 signaling. Allogeneic pancreatic islets transplanted into AC-treated NLRP3-/- mice are not protected, demonstrating that AC requires NLRP3 signaling. Finally, AC also has an immunosuppressive effect on human PBMCs. Overall, our data show that AC establishes an immunosuppressive milieu via the NLRP3/IL-1 axis, leading to trained immunosuppression, or trained tolerance. Our findings give a potent mandate to explore the possibility to target the NLRP3/IL-1 pathway as a new promising strategy to condition transplant recipients and promote allograft tolerance.