Pub Date : 2024-05-30DOI: 10.1016/j.immuni.2024.05.003
Kinan Alhallak, Jun Nagai, Kendall Zaleski, Sofia Marshall, Tamara Salloum, Tahereh Derakhshan, Hiroaki Hayashi, Chunli Feng, Radomir Kratchmarov, Juying Lai, Virinchi Kuchibhotla, Airi Nishida, Barbara Balestrieri, Tanya Laidlaw, Daniel F. Dwyer, Joshua A. Boyce
Severe asthma and sinus disease are consequences of type 2 inflammation (T2I), mediated by interleukin (IL)-33 signaling through its membrane-bound receptor, ST2. Soluble (s)ST2 reduces available IL-33 and limits T2I, but little is known about its regulation. We demonstrate that prostaglandin E2 (PGE2) drives production of sST2 to limit features of lung T2I. PGE2-deficient mice display diminished sST2. In humans with severe respiratory T2I, urinary PGE2 metabolites correlate with serum sST2. In mice, PGE2 enhanced sST2 secretion by mast cells (MCs). Mice lacking MCs, ST2 expression by MCs, or E prostanoid (EP)2 receptors by MCs showed reduced sST2 lung concentrations and strong T2I. Recombinant sST2 reduced T2I in mice lacking PGE2 or ST2 expression by MCs back to control levels. PGE2 deficiency also reversed the hyperinflammatory phenotype in mice lacking ST2 expression by MCs. PGE2 thus suppresses T2I through MC-derived sST2, explaining the severe T2I observed in low PGE2 states.
{"title":"Mast cells control lung type 2 inflammation via prostaglandin E2-driven soluble ST2","authors":"Kinan Alhallak, Jun Nagai, Kendall Zaleski, Sofia Marshall, Tamara Salloum, Tahereh Derakhshan, Hiroaki Hayashi, Chunli Feng, Radomir Kratchmarov, Juying Lai, Virinchi Kuchibhotla, Airi Nishida, Barbara Balestrieri, Tanya Laidlaw, Daniel F. Dwyer, Joshua A. Boyce","doi":"10.1016/j.immuni.2024.05.003","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.05.003","url":null,"abstract":"<p>Severe asthma and sinus disease are consequences of type 2 inflammation (T2I), mediated by interleukin (IL)-33 signaling through its membrane-bound receptor, ST2. Soluble (s)ST2 reduces available IL-33 and limits T2I, but little is known about its regulation. We demonstrate that prostaglandin E<sub>2</sub> (PGE<sub>2</sub>) drives production of sST2 to limit features of lung T2I. PGE<sub>2</sub>-deficient mice display diminished sST2. In humans with severe respiratory T2I, urinary PGE<sub>2</sub> metabolites correlate with serum sST2. In mice, PGE<sub>2</sub> enhanced sST2 secretion by mast cells (MCs). Mice lacking MCs, ST2 expression by MCs, or E prostanoid (EP)<sub>2</sub> receptors by MCs showed reduced sST2 lung concentrations and strong T2I. Recombinant sST2 reduced T2I in mice lacking PGE<sub>2</sub> or ST2 expression by MCs back to control levels. PGE<sub>2</sub> deficiency also reversed the hyperinflammatory phenotype in mice lacking ST2 expression by MCs. PGE<sub>2</sub> thus suppresses T2I through MC-derived sST2, explaining the severe T2I observed in low PGE<sub>2</sub> states.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":null,"pages":null},"PeriodicalIF":32.4,"publicationDate":"2024-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141177924","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-29DOI: 10.1016/j.immuni.2024.05.004
Zhou Liang, Ziwen Tang, Changjian Zhu, Feng Li, Shuaijiabin Chen, Xu Han, Ruilin Zheng, Xinrong Hu, Ruoni Lin, Qiaoqiao Pei, Changjun Yin, Ji Wang, Ce Tang, Nan Cao, Jincun Zhao, Rong Wang, Xiaoyan Li, Ning Luo, Qiong Wen, Jianwen Yu, Yi Zhou
Group 3 innate lymphoid cells (ILC3s) regulate inflammation and tissue repair at mucosal sites, but whether these functions pertain to other tissues—like the kidneys—remains unclear. Here, we observed that renal fibrosis in humans was associated with increased ILC3s in the kidneys and blood. In mice, we showed that CXCR6+ ILC3s rapidly migrated from the intestinal mucosa and accumulated in the kidney via CXCL16 released from the injured tubules. Within the fibrotic kidney, ILC3s increased the expression of programmed cell death-1 (PD-1) and subsequent IL-17A production to directly activate myofibroblasts and fibrotic niche formation. ILC3 expression of PD-1 inhibited IL-23R endocytosis and consequently amplified the JAK2/STAT3/RORγt/IL-17A pathway that was essential for the pro-fibrogenic effect of ILC3s. Thus, we reveal a hitherto unrecognized migration pathway of ILC3s from the intestine to the kidney and the PD-1-dependent function of ILC3s in promoting renal fibrosis.
{"title":"Intestinal CXCR6+ ILC3s migrate to the kidney and exacerbate renal fibrosis via IL-23 receptor signaling enhanced by PD-1 expression","authors":"Zhou Liang, Ziwen Tang, Changjian Zhu, Feng Li, Shuaijiabin Chen, Xu Han, Ruilin Zheng, Xinrong Hu, Ruoni Lin, Qiaoqiao Pei, Changjun Yin, Ji Wang, Ce Tang, Nan Cao, Jincun Zhao, Rong Wang, Xiaoyan Li, Ning Luo, Qiong Wen, Jianwen Yu, Yi Zhou","doi":"10.1016/j.immuni.2024.05.004","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.05.004","url":null,"abstract":"<p>Group 3 innate lymphoid cells (ILC3s) regulate inflammation and tissue repair at mucosal sites, but whether these functions pertain to other tissues—like the kidneys—remains unclear. Here, we observed that renal fibrosis in humans was associated with increased ILC3s in the kidneys and blood. In mice, we showed that CXCR6<sup>+</sup> ILC3s rapidly migrated from the intestinal mucosa and accumulated in the kidney via CXCL16 released from the injured tubules. Within the fibrotic kidney, ILC3s increased the expression of programmed cell death-1 (PD-1) and subsequent IL-17A production to directly activate myofibroblasts and fibrotic niche formation. ILC3 expression of PD-1 inhibited IL-23R endocytosis and consequently amplified the JAK2/STAT3/RORγt/IL-17A pathway that was essential for the pro-fibrogenic effect of ILC3s. Thus, we reveal a hitherto unrecognized migration pathway of ILC3s from the intestine to the kidney and the PD-1-dependent function of ILC3s in promoting renal fibrosis.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":null,"pages":null},"PeriodicalIF":32.4,"publicationDate":"2024-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141177980","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-23DOI: 10.1016/j.immuni.2024.05.001
Irene N. Nkumama, Rodney Ogwang, Dennis Odera, Fauzia Musasia, Kennedy Mwai, Lydia Nyamako, Linda Murungi, James Tuju, Kristin Fürle, Micha Rosenkranz, Rinter Kimathi, Patricia Njuguna, Mainga Hamaluba, Melissa C. Kapulu, Roland Frank, , Faith H.A. Osier
Malaria is a life-threatening disease of global health importance, particularly in sub-Saharan Africa. The growth inhibition assay (GIA) is routinely used to evaluate, prioritize, and quantify the efficacy of malaria blood-stage vaccine candidates but does not reliably predict either naturally acquired or vaccine-induced protection. Controlled human malaria challenge studies in semi-immune volunteers provide an unparalleled opportunity to robustly identify mechanistic correlates of protection. We leveraged this platform to undertake a head-to-head comparison of seven functional antibody assays that are relevant to immunity against the erythrocytic merozoite stage of Plasmodium falciparum. Fc-mediated effector functions were strongly associated with protection from clinical symptoms of malaria and exponential parasite multiplication, while the gold standard GIA was not. The breadth of Fc-mediated effector function discriminated clinical immunity following the challenge. These findings present a shift in the understanding of the mechanisms that underpin immunity to malaria and have important implications for vaccine development.
疟疾是一种威胁生命的疾病,对全球健康具有重要意义,尤其是在撒哈拉以南非洲地区。生长抑素测定 (GIA) 通常用于评估、优先考虑和量化疟疾血期候选疫苗的功效,但不能可靠地预测自然获得或疫苗诱导的保护。在半免疫志愿者中进行的受控人类疟疾挑战研究提供了一个无与伦比的机会,可以有力地确定保护的机理相关因素。我们利用这一平台,对与恶性疟原虫红细胞裂殖阶段免疫相关的七种功能抗体检测进行了正面比较。Fc 介导的效应功能与疟疾临床症状和寄生虫指数繁殖的保护密切相关,而金标准 GIA 则不然。Fc 介导的效应物功能的广度可区分挑战后的临床免疫力。这些发现改变了人们对疟疾免疫机制的认识,对疫苗开发具有重要意义。
{"title":"Breadth of Fc-mediated effector function correlates with clinical immunity following human malaria challenge","authors":"Irene N. Nkumama, Rodney Ogwang, Dennis Odera, Fauzia Musasia, Kennedy Mwai, Lydia Nyamako, Linda Murungi, James Tuju, Kristin Fürle, Micha Rosenkranz, Rinter Kimathi, Patricia Njuguna, Mainga Hamaluba, Melissa C. Kapulu, Roland Frank, , Faith H.A. Osier","doi":"10.1016/j.immuni.2024.05.001","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.05.001","url":null,"abstract":"<p>Malaria is a life-threatening disease of global health importance, particularly in sub-Saharan Africa. The growth inhibition assay (GIA) is routinely used to evaluate, prioritize, and quantify the efficacy of malaria blood-stage vaccine candidates but does not reliably predict either naturally acquired or vaccine-induced protection. Controlled human malaria challenge studies in semi-immune volunteers provide an unparalleled opportunity to robustly identify mechanistic correlates of protection. We leveraged this platform to undertake a head-to-head comparison of seven functional antibody assays that are relevant to immunity against the erythrocytic merozoite stage of <em>Plasmodium falciparum</em>. Fc-mediated effector functions were strongly associated with protection from clinical symptoms of malaria and exponential parasite multiplication, while the gold standard GIA was not. The breadth of Fc-mediated effector function discriminated clinical immunity following the challenge. These findings present a shift in the understanding of the mechanisms that underpin immunity to malaria and have important implications for vaccine development.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":null,"pages":null},"PeriodicalIF":32.4,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141085717","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-23DOI: 10.1016/j.immuni.2024.04.025
Jonathan Mannion, Valentina Gifford, Benjamin Bellenie, Winnie Fernando, Laura Ramos Garcia, Rebecca Wilson, Sidonie Wicky John, Savita Udainiya, Emmanuel C. Patin, Crescens Tiu, Angel Smith, Maria Goicoechea, Andrew Craxton, Nathalia Moraes de Vasconcelos, Naomi Guppy, Kwai-Ming J. Cheung, Nicholas J. Cundy, Olivier Pierrat, Alfie Brennan, Theodoros I. Roumeliotis, Pascal Meier
Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) functions as a critical stress sentinel that coordinates cell survival, inflammation, and immunogenic cell death (ICD). Although the catalytic function of RIPK1 is required to trigger cell death, its non-catalytic scaffold function mediates strong pro-survival signaling. Accordingly, cancer cells can hijack RIPK1 to block necroptosis and evade immune detection. We generated a small-molecule proteolysis-targeting chimera (PROTAC) that selectively degraded human and murine RIPK1. PROTAC-mediated depletion of RIPK1 deregulated TNFR1 and TLR3/4 signaling hubs, accentuating the output of NF-κB, MAPK, and IFN signaling. Additionally, RIPK1 degradation simultaneously promoted RIPK3 activation and necroptosis induction. We further demonstrated that RIPK1 degradation enhanced the immunostimulatory effects of radio- and immunotherapy by sensitizing cancer cells to treatment-induced TNF and interferons. This promoted ICD, antitumor immunity, and durable treatment responses. Consequently, targeting RIPK1 by PROTACs emerges as a promising approach to overcome radio- or immunotherapy resistance and enhance anticancer therapies.
{"title":"A RIPK1-specific PROTAC degrader achieves potent antitumor activity by enhancing immunogenic cell death","authors":"Jonathan Mannion, Valentina Gifford, Benjamin Bellenie, Winnie Fernando, Laura Ramos Garcia, Rebecca Wilson, Sidonie Wicky John, Savita Udainiya, Emmanuel C. Patin, Crescens Tiu, Angel Smith, Maria Goicoechea, Andrew Craxton, Nathalia Moraes de Vasconcelos, Naomi Guppy, Kwai-Ming J. Cheung, Nicholas J. Cundy, Olivier Pierrat, Alfie Brennan, Theodoros I. Roumeliotis, Pascal Meier","doi":"10.1016/j.immuni.2024.04.025","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.04.025","url":null,"abstract":"<p>Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) functions as a critical stress sentinel that coordinates cell survival, inflammation, and immunogenic cell death (ICD). Although the catalytic function of RIPK1 is required to trigger cell death, its non-catalytic scaffold function mediates strong pro-survival signaling. Accordingly, cancer cells can hijack RIPK1 to block necroptosis and evade immune detection. We generated a small-molecule proteolysis-targeting chimera (PROTAC) that selectively degraded human and murine RIPK1. PROTAC-mediated depletion of RIPK1 deregulated TNFR1 and TLR3/4 signaling hubs, accentuating the output of NF-κB, MAPK, and IFN signaling. Additionally, RIPK1 degradation simultaneously promoted RIPK3 activation and necroptosis induction. We further demonstrated that RIPK1 degradation enhanced the immunostimulatory effects of radio- and immunotherapy by sensitizing cancer cells to treatment-induced TNF and interferons. This promoted ICD, antitumor immunity, and durable treatment responses. Consequently, targeting RIPK1 by PROTACs emerges as a promising approach to overcome radio- or immunotherapy resistance and enhance anticancer therapies.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":null,"pages":null},"PeriodicalIF":32.4,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141085788","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-20DOI: 10.1016/j.immuni.2024.04.024
Jiping Sun, Youqin Zhang, Qingbing Zhang, Lin Hu, Linfeng Zhao, Hongdong Wang, Yue Yuan, Hongshen Niu, Dongdi Wang, Huasheng Zhang, Jianyue Liu, Xujiao Feng, Xiaohui Su, Ju Qiu, Jing Sun, Heping Xu, Catherine Zhang, Kathleen Wang, Yan Bi, Edgar G. Engleman, Lei Shen
Adipose tissue group 2 innate lymphoid cells (ILC2s) help maintain metabolic homeostasis by sustaining type 2 immunity and promoting adipose beiging. Although impairment of the ILC2 compartment contributes to obesity-associated insulin resistance, the underlying mechanisms have not been elucidated. Here, we found that ILC2s in obese mice and humans exhibited impaired liver kinase B1 (LKB1) activation. Genetic ablation of LKB1 disrupted ILC2 mitochondrial metabolism and suppressed ILC2 responses, resulting in exacerbated insulin resistance. Mechanistically, LKB1 deficiency induced aberrant PD-1 expression through activation of NFAT, which in turn enhanced mitophagy by suppressing Bcl-xL expression. Blockade of PD-1 restored the normal functions of ILC2s and reversed obesity-induced insulin resistance in mice. Collectively, these data present the LKB1-PD-1 axis as a promising therapeutic target for the treatment of metabolic disease.
{"title":"Metabolic regulator LKB1 controls adipose tissue ILC2 PD-1 expression and mitochondrial homeostasis to prevent insulin resistance","authors":"Jiping Sun, Youqin Zhang, Qingbing Zhang, Lin Hu, Linfeng Zhao, Hongdong Wang, Yue Yuan, Hongshen Niu, Dongdi Wang, Huasheng Zhang, Jianyue Liu, Xujiao Feng, Xiaohui Su, Ju Qiu, Jing Sun, Heping Xu, Catherine Zhang, Kathleen Wang, Yan Bi, Edgar G. Engleman, Lei Shen","doi":"10.1016/j.immuni.2024.04.024","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.04.024","url":null,"abstract":"<p>Adipose tissue group 2 innate lymphoid cells (ILC2s) help maintain metabolic homeostasis by sustaining type 2 immunity and promoting adipose beiging. Although impairment of the ILC2 compartment contributes to obesity-associated insulin resistance, the underlying mechanisms have not been elucidated. Here, we found that ILC2s in obese mice and humans exhibited impaired liver kinase B1 (LKB1) activation. Genetic ablation of LKB1 disrupted ILC2 mitochondrial metabolism and suppressed ILC2 responses, resulting in exacerbated insulin resistance. Mechanistically, LKB1 deficiency induced aberrant PD-1 expression through activation of NFAT, which in turn enhanced mitophagy by suppressing Bcl-xL expression. Blockade of PD-1 restored the normal functions of ILC2s and reversed obesity-induced insulin resistance in mice. Collectively, these data present the LKB1-PD-1 axis as a promising therapeutic target for the treatment of metabolic disease.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":null,"pages":null},"PeriodicalIF":32.4,"publicationDate":"2024-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141069219","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-20DOI: 10.1016/j.immuni.2024.04.022
Ipsita Subudhi, Piotr Konieczny, Aleksandr Prystupa, Rochelle L. Castillo, Erica Sze-Tu, Yue Xing, Daniel Rosenblum, Ilana Reznikov, Ikjot Sidhu, Cynthia Loomis, Catherine P. Lu, Niroshana Anandasabapathy, Mayte Suárez-Fariñas, Johann E. Gudjonsson, Aristotelis Tsirigos, Jose U. Scher, Shruti Naik
Inflammatory epithelial diseases are spurred by the concomitant dysregulation of immune and epithelial cells. How these two dysregulated cellular compartments simultaneously sustain their heightened metabolic demands is unclear. Single-cell and spatial transcriptomics (ST), along with immunofluorescence, revealed that hypoxia-inducible factor 1α (HIF1α), downstream of IL-17 signaling, drove psoriatic epithelial remodeling. Blocking HIF1α in human psoriatic lesions ex vivo impaired glycolysis and phenocopied anti-IL-17 therapy. In a murine model of skin inflammation, epidermal-specific loss of HIF1α or its target gene, glucose transporter 1, ameliorated epidermal, immune, vascular, and neuronal pathology. Mechanistically, glycolysis autonomously fueled epithelial pathology and enhanced lactate production, which augmented the γδ T17 cell response. RORγt-driven genetic deletion or pharmacological inhibition of either lactate-producing enzymes or lactate transporters attenuated epithelial pathology and IL-17A expression in vivo. Our findings identify a metabolic hierarchy between epithelial and immune compartments and the consequent coordination of metabolic processes that sustain inflammatory disease.
{"title":"Metabolic coordination between skin epithelium and type 17 immunity sustains chronic skin inflammation","authors":"Ipsita Subudhi, Piotr Konieczny, Aleksandr Prystupa, Rochelle L. Castillo, Erica Sze-Tu, Yue Xing, Daniel Rosenblum, Ilana Reznikov, Ikjot Sidhu, Cynthia Loomis, Catherine P. Lu, Niroshana Anandasabapathy, Mayte Suárez-Fariñas, Johann E. Gudjonsson, Aristotelis Tsirigos, Jose U. Scher, Shruti Naik","doi":"10.1016/j.immuni.2024.04.022","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.04.022","url":null,"abstract":"<p>Inflammatory epithelial diseases are spurred by the concomitant dysregulation of immune and epithelial cells. How these two dysregulated cellular compartments simultaneously sustain their heightened metabolic demands is unclear. Single-cell and spatial transcriptomics (ST), along with immunofluorescence, revealed that hypoxia-inducible factor 1α (HIF1α), downstream of IL-17 signaling, drove psoriatic epithelial remodeling. Blocking HIF1α in human psoriatic lesions <em>ex vivo</em> impaired glycolysis and phenocopied anti-IL-17 therapy. In a murine model of skin inflammation, epidermal-specific loss of HIF1α or its target gene, glucose transporter 1, ameliorated epidermal, immune, vascular, and neuronal pathology. Mechanistically, glycolysis autonomously fueled epithelial pathology and enhanced lactate production, which augmented the γδ T17 cell response. RORγt-driven genetic deletion or pharmacological inhibition of either lactate-producing enzymes or lactate transporters attenuated epithelial pathology and IL-17A expression <em>in vivo</em>. Our findings identify a metabolic hierarchy between epithelial and immune compartments and the consequent coordination of metabolic processes that sustain inflammatory disease.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":null,"pages":null},"PeriodicalIF":32.4,"publicationDate":"2024-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141069217","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-17DOI: 10.1016/j.immuni.2024.04.023
Xin Li, Weili Sun, Mengxing Huang, Liying Gong, Xiaochen Zhang, Li Zhong, Virginie Calderon, Zhenhua Bian, Yi He, Woong-Kyung Suh, Yang Li, Tengfei Song, Yongrui Zou, Zhe-Xiong Lian, Hua Gu
Recent evidence reveals hyper T follicular helper (Tfh) cell responses in systemic lupus erythematosus (SLE); however, molecular mechanisms responsible for hyper Tfh cell responses and whether they cause SLE are unclear. We found that SLE patients downregulated both ubiquitin ligases, casitas B-lineage lymphoma (CBL) and CBLB (CBLs), in CD4+ T cells. T cell-specific CBLs-deficient mice developed hyper Tfh cell responses and SLE, whereas blockade of Tfh cell development in the mutant mice was sufficient to prevent SLE. ICOS was upregulated in SLE Tfh cells, whose signaling increased BCL6 by attenuating BCL6 degradation via chaperone-mediated autophagy (CMA). Conversely, CBLs restrained BCL6 expression by ubiquitinating ICOS. Blockade of BCL6 degradation was sufficient to enhance Tfh cell responses. Thus, the compromised expression of CBLs is a prevalent risk trait shared by SLE patients and causative to hyper Tfh cell responses and SLE. The ICOS-CBLs axis may be a target to treat SLE.
{"title":"Deficiency of CBL and CBLB ubiquitin ligases leads to hyper T follicular helper cell responses and lupus by reducing BCL6 degradation","authors":"Xin Li, Weili Sun, Mengxing Huang, Liying Gong, Xiaochen Zhang, Li Zhong, Virginie Calderon, Zhenhua Bian, Yi He, Woong-Kyung Suh, Yang Li, Tengfei Song, Yongrui Zou, Zhe-Xiong Lian, Hua Gu","doi":"10.1016/j.immuni.2024.04.023","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.04.023","url":null,"abstract":"<p>Recent evidence reveals hyper T follicular helper (Tfh) cell responses in systemic lupus erythematosus (SLE); however, molecular mechanisms responsible for hyper Tfh cell responses and whether they cause SLE are unclear. We found that SLE patients downregulated both ubiquitin ligases, casitas B-lineage lymphoma (CBL) and CBLB (CBLs), in CD4<sup>+</sup> T cells. T cell-specific CBLs-deficient mice developed hyper Tfh cell responses and SLE, whereas blockade of Tfh cell development in the mutant mice was sufficient to prevent SLE. ICOS was upregulated in SLE Tfh cells, whose signaling increased BCL6 by attenuating BCL6 degradation via chaperone-mediated autophagy (CMA). Conversely, CBLs restrained BCL6 expression by ubiquitinating ICOS. Blockade of BCL6 degradation was sufficient to enhance Tfh cell responses. Thus, the compromised expression of CBLs is a prevalent risk trait shared by SLE patients and causative to hyper Tfh cell responses and SLE. The ICOS-CBLs axis may be a target to treat SLE.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":null,"pages":null},"PeriodicalIF":32.4,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140954524","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-15DOI: 10.1016/j.immuni.2024.04.017
Neetu Srivastava, Hao Hu, Orion J. Peterson, Anthony N. Vomund, Marta Stremska, Mohammad Zaman, Shilpi Giri, Tiandao Li, Cheryl F. Lichti, Pavel N. Zakharov, Bo Zhang, Nada A. Abumrad, Yi-Guang Chen, Kodi S. Ravichandran, Emil R. Unanue, Xiaoxiao Wan
The pancreatic islet microenvironment is highly oxidative, rendering β cells vulnerable to autoinflammatory insults. Here, we examined the role of islet resident macrophages in the autoimmune attack that initiates type 1 diabetes. Islet macrophages highly expressed CXCL16, a chemokine and scavenger receptor for oxidized low-density lipoproteins (OxLDLs), regardless of autoimmune predisposition. Deletion of Cxcl16 in nonobese diabetic (NOD) mice suppressed the development of autoimmune diabetes. Mechanistically, Cxcl16 deficiency impaired clearance of OxLDL by islet macrophages, leading to OxLDL accumulation in pancreatic islets and a substantial reduction in intra-islet transitory (Texint) CD8+ T cells displaying proliferative and effector signatures. Texint cells were vulnerable to oxidative stress and diminished by ferroptosis; PD-1 blockade rescued this population and reversed diabetes resistance in NOD.Cxcl16−/− mice. Thus, OxLDL scavenging in pancreatic islets inadvertently promotes differentiation of pathogenic CD8+ T cells, presenting a paradigm wherein tissue homeostasis processes can facilitate autoimmune pathogenesis in predisposed individuals.
胰岛微环境具有高度氧化性,使β细胞容易受到自身炎症的损伤。在此,我们研究了胰岛巨噬细胞在引发1型糖尿病的自身免疫攻击中的作用。胰岛巨噬细胞高度表达CXCL16,这是一种趋化因子,也是氧化低密度脂蛋白(OxLDLs)的清除受体,与自身免疫倾向无关。在非肥胖糖尿病(NOD)小鼠体内删除 Cxcl16 可抑制自身免疫性糖尿病的发生。从机理上讲,Cxcl16的缺失损害了胰岛巨噬细胞对OxLDL的清除,导致OxLDL在胰岛中积聚,并使胰岛内具有增殖和效应特征的CD8+T细胞大幅减少。Texint细胞容易受到氧化应激的影响,并因铁蛋白沉积而减少;PD-1阻断可挽救这一细胞群,并逆转NOD.Cxcl16-/-小鼠的糖尿病抵抗。因此,胰岛中的氧化低密度脂蛋白清除无意中促进了致病性 CD8+ T 细胞的分化,从而提出了一种范例,即组织稳态过程可促进易感个体的自身免疫发病机制。
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Pub Date : 2024-05-14DOI: 10.1016/j.immuni.2024.04.013
Shannon McCarthy, Judith Agudo
Stem cells heal wounds. In this issue of Immunity, Luan et al. demonstrate that epidermal stem cells orchestrate the recruitment of regulatory T (Treg) cells and neutrophils during wound healing. Treg cells facilitate a tolerogenic environment to protect epithelial regeneration while neutrophils promote inflammation to ward off infection.
{"title":"Hair care: Stem cells control immune response during wound repair","authors":"Shannon McCarthy, Judith Agudo","doi":"10.1016/j.immuni.2024.04.013","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.04.013","url":null,"abstract":"<p>Stem cells heal wounds. In this issue of <em>Immunity</em>, Luan et al. demonstrate that epidermal stem cells orchestrate the recruitment of regulatory T (Treg) cells and neutrophils during wound healing. Treg cells facilitate a tolerogenic environment to protect epithelial regeneration while neutrophils promote inflammation to ward off infection.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":null,"pages":null},"PeriodicalIF":32.4,"publicationDate":"2024-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140920011","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-14DOI: 10.1016/j.immuni.2024.04.008
Leo Nicolai, Kami Pekayvaz, Steffen Massberg
Platelets prevent blood loss during vascular injury and contribute to thrombus formation in cardiovascular disease. Beyond these classical roles, platelets are critical for the host immune response. They guard the vasculature against pathogens via specialized receptors, intracellular signaling cascades, and effector functions. Platelets also skew inflammatory responses by instructing innate immune cells, support adaptive immunosurveillance, and influence antibody production and T cell polarization. Concomitantly, platelets contribute to tissue reconstitution and maintain vascular function after inflammatory challenges. However, dysregulated activation of these multitalented cells exacerbates immunopathology with ensuing microvascular clotting, excessive inflammation, and elevated risk of macrovascular thrombosis. This dichotomy underscores the critical importance of precisely defining and potentially modulating platelet function in immunity.
血小板可防止血管损伤时的血液流失,并有助于心血管疾病中血栓的形成。除了这些传统作用外,血小板对宿主免疫反应也至关重要。它们通过专门的受体、细胞内信号级联和效应器功能保护血管免受病原体侵袭。血小板还能通过指示先天性免疫细胞、支持适应性免疫监视、影响抗体产生和 T 细胞极化来歪曲炎症反应。同时,血小板还有助于组织重建,并在炎症挑战后维持血管功能。然而,这些多才多艺细胞的失调激活会加剧免疫病理,导致微血管凝血、过度炎症和大血管血栓风险升高。这种对立强调了精确定义和潜在调节免疫中血小板功能的极端重要性。
{"title":"Platelets: Orchestrators of immunity in host defense and beyond","authors":"Leo Nicolai, Kami Pekayvaz, Steffen Massberg","doi":"10.1016/j.immuni.2024.04.008","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.04.008","url":null,"abstract":"<p>Platelets prevent blood loss during vascular injury and contribute to thrombus formation in cardiovascular disease. Beyond these classical roles, platelets are critical for the host immune response. They guard the vasculature against pathogens via specialized receptors, intracellular signaling cascades, and effector functions. Platelets also skew inflammatory responses by instructing innate immune cells, support adaptive immunosurveillance, and influence antibody production and T cell polarization. Concomitantly, platelets contribute to tissue reconstitution and maintain vascular function after inflammatory challenges. However, dysregulated activation of these multitalented cells exacerbates immunopathology with ensuing microvascular clotting, excessive inflammation, and elevated risk of macrovascular thrombosis. This dichotomy underscores the critical importance of precisely defining and potentially modulating platelet function in immunity.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":null,"pages":null},"PeriodicalIF":32.4,"publicationDate":"2024-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140920048","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}