Pub Date : 2024-08-06DOI: 10.1016/j.immuni.2024.07.010
The master transcription factor of regulatory T (Treg) cells, forkhead box protein P3 (Foxp3), controls Treg cell function by targeting certain genes for activation or repression, but the specific mechanisms by which it mediates this activation or repression under different conditions remain unclear. We found that Ikzf1 associates with Foxp3 via its exon 5 (IkE5) and that IkE5-deficient Treg cells highly expressed genes that would otherwise be repressed by Foxp3 upon T cell receptor stimulation, including Ifng. Treg-specific IkE5-deletion caused interferon-γ (IFN-γ) overproduction, which destabilized Foxp3 expression and impaired Treg suppressive function, leading to systemic autoimmune disease and strong anti-tumor immunity. Pomalidomide, which degrades IKZF1 and IKZF3, induced IFN-γ overproduction in human Treg cells. Mechanistically, the Foxp3-Ikzf1-Ikzf3 complex competed with epigenetic co-activators, such as p300, for binding to target gene loci via chromatin remodeling. Therefore, the Ikzf1 association with Foxp3 is essential for the gene-repressive function of Foxp3 and could be exploited to treat autoimmune disease and cancer.
{"title":"Transcription factor Ikzf1 associates with Foxp3 to repress gene expression in Treg cells and limit autoimmunity and anti-tumor immunity","authors":"","doi":"10.1016/j.immuni.2024.07.010","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.07.010","url":null,"abstract":"<p>The master transcription factor of regulatory T (Treg) cells, forkhead box protein P3 (Foxp3), controls Treg cell function by targeting certain genes for activation or repression, but the specific mechanisms by which it mediates this activation or repression under different conditions remain unclear. We found that Ikzf1 associates with Foxp3 via its exon 5 (IkE5) and that <em>IkE5</em>-deficient Treg cells highly expressed genes that would otherwise be repressed by Foxp3 upon T cell receptor stimulation, including <em>Ifng</em>. Treg-specific <em>IkE5</em>-deletion caused interferon-γ (IFN-γ) overproduction, which destabilized Foxp3 expression and impaired Treg suppressive function, leading to systemic autoimmune disease and strong anti-tumor immunity. Pomalidomide, which degrades IKZF1 and IKZF3, induced IFN-γ overproduction in human Treg cells. Mechanistically, the Foxp3-Ikzf1-Ikzf3 complex competed with epigenetic co-activators, such as p300, for binding to target gene loci via chromatin remodeling. Therefore, the Ikzf1 association with Foxp3 is essential for the gene-repressive function of Foxp3 and could be exploited to treat autoimmune disease and cancer.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"190 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141895864","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 : 2024-08-02DOI: 10.1016/j.immuni.2024.07.006
Naive CD4+ T cells in specific pathogen-free (SPF) mice are characterized by transcriptional heterogeneity and subpopulations distinguished by the expression of quiescence, the extracellular matrix (ECM) and cytoskeleton, type I interferon (IFN-I) response, memory-like, and T cell receptor (TCR) activation genes. We demonstrate that this constitutive heterogeneity, including the presence of the IFN-I response cluster, is commensal independent insofar as being identical in germ-free and SPF mice. By contrast, Nippostrongylus brasiliensis infection altered this constitutive heterogeneity. Naive T cell-intrinsic transcriptional changes acquired during helminth infection correlated with and accounted for decreased immunization response to an unrelated antigen. These compositional and functional changes were dependent variables of helminth infection, as they disappeared at the established time point of its clearance in mice. Collectively, our results indicate that the naive T cell pool is subject to dynamic transcriptional changes in response to certain environmental cues, which in turn permutes the magnitude of the immune response.
无特异性病原体(SPF)小鼠的幼稚 CD4+ T 细胞具有转录异质性和亚群特征,这些亚群通过静止、细胞外基质(ECM)和细胞骨架、I 型干扰素(IFN-I)反应、记忆样和 T 细胞受体(TCR)激活基因的表达来区分。我们证明,这种构成性异质性,包括 IFN-I 反应群的存在,与无菌小鼠和 SPF 小鼠中的共生体无关。与此相反,巴西镍丝虫感染改变了这种组成异质性。在蠕虫感染期间获得的幼稚T细胞内在转录变化与对无关抗原的免疫反应下降相关,并说明了这一点。这些组成和功能变化是蠕虫感染的因变量,因为它们在小鼠体内清除蠕虫的既定时间点消失了。总之,我们的研究结果表明,天真 T 细胞池会因某些环境线索而发生动态转录变化,进而改变免疫反应的程度。
{"title":"The amalgam of naive CD4+ T cell transcriptional states is reconfigured by helminth infection to dampen the amplitude of the immune response","authors":"","doi":"10.1016/j.immuni.2024.07.006","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.07.006","url":null,"abstract":"<p>Naive CD4<sup>+</sup> T cells in specific pathogen-free (SPF) mice are characterized by transcriptional heterogeneity and subpopulations distinguished by the expression of quiescence, the extracellular matrix (ECM) and cytoskeleton, type I interferon (IFN-I) response, memory-like, and T cell receptor (TCR) activation genes. We demonstrate that this constitutive heterogeneity, including the presence of the IFN-I response cluster, is commensal independent insofar as being identical in germ-free and SPF mice. By contrast, <em>Nippostrongylus brasiliensis</em> infection altered this constitutive heterogeneity. Naive T cell-intrinsic transcriptional changes acquired during helminth infection correlated with and accounted for decreased immunization response to an unrelated antigen. These compositional and functional changes were dependent variables of helminth infection, as they disappeared at the established time point of its clearance in mice. Collectively, our results indicate that the naive T cell pool is subject to dynamic transcriptional changes in response to certain environmental cues, which in turn permutes the magnitude of the immune response.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"38 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141877593","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 : 2024-07-31DOI: 10.1016/j.immuni.2024.07.005
Unlike sessile macrophages that occupy specialized tissue niches, non-classical monocytes (NCMs)—circulating phagocytes that patrol and cleanse the luminal surface of the vascular tree—are characterized by constant movement. Here, we examined the nature of the NCM’s nurturing niche. Expression of the growth factor CSF1 on endothelial cells was required for survival of NCMs in the bloodstream. Lack of endothelial-derived CSF1 did not affect blood CSF1 concentration, suggesting that NCMs rely on scavenging CSF1 present on endothelial cells. Deletion of the transmembrane chemokine and adhesion factor CX3CL1 on endothelial cells impaired NCM survival. Mechanistically, endothelial-derived CX3CL1 and integrin subunit alpha L (ITGAL) facilitated the uptake of CSF1 by NCMs. CSF1 was produced by all tissular endothelial cells, and deletion of Csf1 in all endothelial cells except bone marrow sinusoids impaired NCM survival, arguing for a model where the full vascular tree acts as a niche for NCMs and where survival and patrolling function are connected.
{"title":"Non-classical monocytes scavenge the growth factor CSF1 from endothelial cells in the peripheral vascular tree to ensure survival and homeostasis","authors":"","doi":"10.1016/j.immuni.2024.07.005","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.07.005","url":null,"abstract":"<p>Unlike sessile macrophages that occupy specialized tissue niches, non-classical monocytes (NCMs)—circulating phagocytes that patrol and cleanse the luminal surface of the vascular tree—are characterized by constant movement. Here, we examined the nature of the NCM’s nurturing niche. Expression of the growth factor CSF1 on endothelial cells was required for survival of NCMs in the bloodstream. Lack of endothelial-derived CSF1 did not affect blood CSF1 concentration, suggesting that NCMs rely on scavenging CSF1 present on endothelial cells. Deletion of the transmembrane chemokine and adhesion factor CX3CL1 on endothelial cells impaired NCM survival. Mechanistically, endothelial-derived CX3CL1 and integrin subunit alpha L (ITGAL) facilitated the uptake of CSF1 by NCMs. CSF1 was produced by all tissular endothelial cells, and deletion of <em>Csf1</em> in all endothelial cells except bone marrow sinusoids impaired NCM survival, arguing for a model where the full vascular tree acts as a niche for NCMs and where survival and patrolling function are connected.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"8 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141858007","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 : 2024-07-29DOI: 10.1016/j.immuni.2024.07.002
Stroke leads to persistently high risk for recurrent vascular events caused by systemic atheroprogression that is driven by endothelial cell (EC) activation. However, whether and how stroke induces sustained pro-inflammatory and proatherogenic endothelial alterations in systemic vessels remain poorly understood. We showed that brain ischemia induces persistent activation, the upregulation of adhesion molecule VCAM1, and increased senescence in peripheral ECs until 4 weeks after stroke onset. This aberrant EC activity resulted from sustained Notch1 signaling, which was triggered by increased circulating Notch1 ligands DLL1 and Jagged1 after stroke in mice and humans. Consequently, this led to increased myeloid cell adhesion and atheroprogression by generating a senescent, pro-inflammatory endothelium. Notch1- or VCAM1-blocking antibodies and the genetic ablation of endothelial Notch1 reduced atheroprogression after stroke. Our findings revealed a systemic machinery that induces the persistent activation of peripheral ECs after stroke, which paves the way for therapeutic interventions or the prevention of recurrent vascular events following stroke.
{"title":"Brain ischemia causes systemic Notch1 activity in endothelial cells to drive atherosclerosis","authors":"","doi":"10.1016/j.immuni.2024.07.002","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.07.002","url":null,"abstract":"<p>Stroke leads to persistently high risk for recurrent vascular events caused by systemic atheroprogression that is driven by endothelial cell (EC) activation. However, whether and how stroke induces sustained pro-inflammatory and proatherogenic endothelial alterations in systemic vessels remain poorly understood. We showed that brain ischemia induces persistent activation, the upregulation of adhesion molecule VCAM1, and increased senescence in peripheral ECs until 4 weeks after stroke onset. This aberrant EC activity resulted from sustained Notch1 signaling, which was triggered by increased circulating Notch1 ligands DLL1 and Jagged1 after stroke in mice and humans. Consequently, this led to increased myeloid cell adhesion and atheroprogression by generating a senescent, pro-inflammatory endothelium. Notch1- or VCAM1-blocking antibodies and the genetic ablation of endothelial Notch1 reduced atheroprogression after stroke. Our findings revealed a systemic machinery that induces the persistent activation of peripheral ECs after stroke, which paves the way for therapeutic interventions or the prevention of recurrent vascular events following stroke.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"22 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141795034","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 : 2024-07-29DOI: 10.1016/j.immuni.2024.07.004
In squamous cell carcinoma (SCC), macrophages responding to interleukin (IL)-33 create a TGF-β-rich stromal niche that maintains cancer stem cells (CSCs), which evade chemotherapy-induced apoptosis in part via activation of the NRF2 antioxidant program. Here, we examined how IL-33 derived from CSCs facilitates the development of an immunosuppressive microenvironment. CSCs with high NRF2 activity redistributed nuclear IL-33 to the cytoplasm and released IL-33 as cargo of large oncosomes (LOs). Mechanistically, NRF2 increased the expression of the lipid scramblase ATG9B, which exposed an “eat me” signal on the LO surface, leading to annexin A1 (ANXA1) loading. These LOs promoted the differentiation of AXNA1 receptor+ myeloid precursors into immunosuppressive macrophages. Blocking ATG9B’s scramblase activity or depleting ANXA1 decreased niche macrophages and hindered tumor progression. Thus, IL-33 is released from live CSCs via LOs to promote the differentiation of alternatively activated macrophage, with potential relevance to other settings of inflammation and tissue repair.
{"title":"Cancer stem cells release interleukin-33 within large oncosomes to promote immunosuppressive differentiation of macrophage precursors","authors":"","doi":"10.1016/j.immuni.2024.07.004","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.07.004","url":null,"abstract":"<p>In squamous cell carcinoma (SCC), macrophages responding to interleukin (IL)-33 create a TGF-β-rich stromal niche that maintains cancer stem cells (CSCs), which evade chemotherapy-induced apoptosis in part via activation of the NRF2 antioxidant program. Here, we examined how IL-33 derived from CSCs facilitates the development of an immunosuppressive microenvironment. CSCs with high NRF2 activity redistributed nuclear IL-33 to the cytoplasm and released IL-33 as cargo of large oncosomes (LOs). Mechanistically, NRF2 increased the expression of the lipid scramblase ATG9B, which exposed an “eat me” signal on the LO surface, leading to annexin A1 (ANXA1) loading. These LOs promoted the differentiation of AXNA1 receptor<sup>+</sup> myeloid precursors into immunosuppressive macrophages. Blocking ATG9B’s scramblase activity or depleting ANXA1 decreased niche macrophages and hindered tumor progression. Thus, IL-33 is released from live CSCs via LOs to promote the differentiation of alternatively activated macrophage, with potential relevance to other settings of inflammation and tissue repair.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"7 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141795032","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 : 2024-07-24DOI: 10.1016/j.immuni.2024.07.001
The reduced ability of the central nervous system to regenerate with increasing age limits functional recovery following demyelinating injury. Previous work has shown that myelin debris can overwhelm the metabolic capacity of microglia, thereby impeding tissue regeneration in aging, but the underlying mechanisms are unknown. In a model of demyelination, we found that a substantial number of genes that were not effectively activated in aged myeloid cells displayed epigenetic modifications associated with restricted chromatin accessibility. Ablation of two class I histone deacetylases in microglia was sufficient to restore the capacity of aged mice to remyelinate lesioned tissue. We used Bacillus Calmette-Guerin (BCG), a live-attenuated vaccine, to train the innate immune system and detected epigenetic reprogramming of brain-resident myeloid cells and functional restoration of myelin debris clearance and lesion recovery. Our results provide insight into aging-associated decline in myeloid function and how this decay can be prevented by innate immune reprogramming.
{"title":"Innate immune training restores pro-reparative myeloid functions to promote remyelination in the aged central nervous system","authors":"","doi":"10.1016/j.immuni.2024.07.001","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.07.001","url":null,"abstract":"<p>The reduced ability of the central nervous system to regenerate with increasing age limits functional recovery following demyelinating injury. Previous work has shown that myelin debris can overwhelm the metabolic capacity of microglia, thereby impeding tissue regeneration in aging, but the underlying mechanisms are unknown. In a model of demyelination, we found that a substantial number of genes that were not effectively activated in aged myeloid cells displayed epigenetic modifications associated with restricted chromatin accessibility. Ablation of two class I histone deacetylases in microglia was sufficient to restore the capacity of aged mice to remyelinate lesioned tissue. We used Bacillus Calmette-Guerin (BCG), a live-attenuated vaccine, to train the innate immune system and detected epigenetic reprogramming of brain-resident myeloid cells and functional restoration of myelin debris clearance and lesion recovery. Our results provide insight into aging-associated decline in myeloid function and how this decay can be prevented by innate immune reprogramming.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"15 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141754582","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 : 2024-07-23DOI: 10.1016/j.immuni.2024.06.015
Tissue adaptation is required for regulatory T (Treg) cell function within organs. Whether this program shares aspects with other tissue-localized immune populations is unclear. Here, we analyzed single-cell chromatin accessibility data, including the transposable element (TE) landscape of CD45+ immune cells from colon, skin, adipose tissue, and spleen. We identified features of organ-specific tissue adaptation across different immune cells. Focusing on tissue Treg cells, we found conservation of the Treg tissue adaptation program in other tissue-localized immune cells, such as amphiregulin-producing T helper (Th)17 cells. Accessible TEs can act as regulatory elements, but their contribution to tissue adaptation is not understood. TE landscape analysis revealed an enrichment of specific transcription factor binding motifs in TE regions within accessible chromatin peaks. TEs, specifically from the LTR family, were located in enhancer regions and associated with tissue adaptation. These findings broaden our understanding of immune tissue residency and provide an important step toward organ-specific immune interventions.
{"title":"Single-cell chromatin accessibility and transposable element landscapes reveal shared features of tissue-residing immune cells","authors":"","doi":"10.1016/j.immuni.2024.06.015","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.06.015","url":null,"abstract":"<p>Tissue adaptation is required for regulatory T (Treg) cell function within organs. Whether this program shares aspects with other tissue-localized immune populations is unclear. Here, we analyzed single-cell chromatin accessibility data, including the transposable element (TE) landscape of CD45<sup>+</sup> immune cells from colon, skin, adipose tissue, and spleen. We identified features of organ-specific tissue adaptation across different immune cells. Focusing on tissue Treg cells, we found conservation of the Treg tissue adaptation program in other tissue-localized immune cells, such as amphiregulin-producing T helper (Th)17 cells. Accessible TEs can act as regulatory elements, but their contribution to tissue adaptation is not understood. TE landscape analysis revealed an enrichment of specific transcription factor binding motifs in TE regions within accessible chromatin peaks. TEs, specifically from the LTR family, were located in enhancer regions and associated with tissue adaptation. These findings broaden our understanding of immune tissue residency and provide an important step toward organ-specific immune interventions.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"22 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141754583","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 : 2024-07-22DOI: 10.1016/j.immuni.2024.06.016
Lung-tissue-resident memory (TRM) CD8+ T cells are critical for heterosubtypic immunity against influenza virus (IAV) reinfection. How TRM cells surveil the lung, respond to infection, and interact with other cells remains unresolved. Here, we used IAV infection of mice in combination with intravital and static imaging to define the spatiotemporal dynamics of lung TRM cells before and after recall infection. CD69+CD103+ TRM cells preferentially localized to lung sites of prior IAV infection, where they exhibited patrolling behavior. After rechallenge, lung TRM cells formed tight clusters in an antigen-dependent manner. Transcriptomic analysis of IAV-specific TRM cells revealed the expression of several factors that regulate myeloid cell biology. In vivo rechallenge experiments demonstrated that protection elicited by TRM cells is orchestrated in part by interferon (IFN)-γ-mediated recruitment of inflammatory monocytes into the lungs. Overall, these data illustrate the dynamic landscapes of CD103+ lung TRM cells that mediate early protective immunity against IAV infection.
{"title":"Dynamic landscapes and protective immunity coordinated by influenza-specific lung-resident memory CD8+ T cells revealed by intravital imaging","authors":"","doi":"10.1016/j.immuni.2024.06.016","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.06.016","url":null,"abstract":"<p>Lung-tissue-resident memory (T<sub>RM</sub>) CD8<sup>+</sup> T cells are critical for heterosubtypic immunity against influenza virus (IAV) reinfection. How T<sub>RM</sub> cells surveil the lung, respond to infection, and interact with other cells remains unresolved. Here, we used IAV infection of mice in combination with intravital and static imaging to define the spatiotemporal dynamics of lung T<sub>RM</sub> cells before and after recall infection. CD69<sup>+</sup>CD103<sup>+</sup> T<sub>RM</sub> cells preferentially localized to lung sites of prior IAV infection, where they exhibited patrolling behavior. After rechallenge, lung T<sub>RM</sub> cells formed tight clusters in an antigen-dependent manner. Transcriptomic analysis of IAV-specific T<sub>RM</sub> cells revealed the expression of several factors that regulate myeloid cell biology. <em>In vivo</em> rechallenge experiments demonstrated that protection elicited by T<sub>RM</sub> cells is orchestrated in part by interferon (IFN)-γ-mediated recruitment of inflammatory monocytes into the lungs. Overall, these data illustrate the dynamic landscapes of CD103<sup>+</sup> lung T<sub>RM</sub> cells that mediate early protective immunity against IAV infection.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"26 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141746538","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 : 2024-07-22DOI: 10.1016/j.immuni.2024.06.014
The memory CD8+ T cell pool contains phenotypically and transcriptionally heterogeneous subsets with specialized functions and recirculation patterns. Here, we examined the epigenetic landscape of CD8+ T cells isolated from seven non-lymphoid organs across four distinct infection models, alongside their circulating T cell counterparts. Using single-cell transposase-accessible chromatin sequencing (scATAC-seq), we found that tissue-resident memory T (TRM) cells and circulating memory T (TCIRC) cells develop along distinct epigenetic trajectories. We identified organ-specific transcriptional regulators of TRM cell development, including FOSB, FOS, FOSL1, and BACH2, and defined an epigenetic signature common to TRM cells across organs. Finally, we found that although terminal TEX cells share accessible regulatory elements with TRM cells, they are defined by TEX-specific epigenetic features absent from TRM cells. Together, this comprehensive data resource shows that TRM cell development is accompanied by dynamic transcriptome alterations and chromatin accessibility changes that direct tissue-adapted and functionally distinct T cell states.
记忆性 CD8+ T 细胞池包含表型和转录异质性亚群,具有专门的功能和再循环模式。在这里,我们研究了在四种不同的感染模型中从七个非淋巴器官中分离出来的 CD8+ T 细胞的表观遗传学景观,以及它们的循环 T 细胞对应物。利用单细胞转座酶可获取染色质测序(scATAC-seq),我们发现组织驻留记忆T细胞(TRM)和循环记忆T细胞(TCIRC)沿着不同的表观遗传学轨迹发展。我们确定了TRM细胞发育的器官特异性转录调控因子,包括FOSB、FOS、FOSL1和BACH2,并定义了各器官TRM细胞共有的表观遗传学特征。最后,我们发现尽管末端TEX细胞与TRM细胞共享可访问的调控元件,但它们是由TRM细胞所没有的TEX特异性表观遗传特征所定义的。总之,这一全面的数据资源表明,TRM 细胞的发育伴随着动态转录组的改变和染色质可及性的改变,这些改变引导着组织适应性和功能上不同的 T 细胞状态。
{"title":"Distinct epigenomic landscapes underlie tissue-specific memory T cell differentiation","authors":"","doi":"10.1016/j.immuni.2024.06.014","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.06.014","url":null,"abstract":"<p>The memory CD8<sup>+</sup> T cell pool contains phenotypically and transcriptionally heterogeneous subsets with specialized functions and recirculation patterns. Here, we examined the epigenetic landscape of CD8<sup>+</sup> T cells isolated from seven non-lymphoid organs across four distinct infection models, alongside their circulating T cell counterparts. Using single-cell transposase-accessible chromatin sequencing (scATAC-seq), we found that tissue-resident memory T (T<sub>RM</sub>) cells and circulating memory T (T<sub>CIRC</sub>) cells develop along distinct epigenetic trajectories. We identified organ-specific transcriptional regulators of T<sub>RM</sub> cell development, including FOSB, FOS, FOSL1, and BACH2, and defined an epigenetic signature common to T<sub>RM</sub> cells across organs. Finally, we found that although terminal T<sub>EX</sub> cells share accessible regulatory elements with T<sub>RM</sub> cells, they are defined by T<sub>EX</sub>-specific epigenetic features absent from T<sub>RM</sub> cells. Together, this comprehensive data resource shows that T<sub>RM</sub> cell development is accompanied by dynamic transcriptome alterations and chromatin accessibility changes that direct tissue-adapted and functionally distinct T cell states.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"8 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141746537","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 : 2024-07-15DOI: 10.1016/j.immuni.2024.06.013
Lassa virus is estimated to cause thousands of human deaths per year, primarily due to spillovers from its natural host, Mastomys rodents. Efforts to create vaccines and antibody therapeutics must account for the evolutionary variability of the Lassa virus’s glycoprotein complex (GPC), which mediates viral entry into cells and is the target of neutralizing antibodies. To map the evolutionary space accessible to GPC, we used pseudovirus deep mutational scanning to measure how nearly all GPC amino-acid mutations affected cell entry and antibody neutralization. Our experiments defined functional constraints throughout GPC. We quantified how GPC mutations affected neutralization with a panel of monoclonal antibodies. All antibodies tested were escaped by mutations that existed among natural Lassa virus lineages. Overall, our work describes a biosafety-level-2 method to elucidate the mutational space accessible to GPC and shows how prospective characterization of antigenic variation could aid the design of therapeutics and vaccines.
{"title":"Deep mutational scanning reveals functional constraints and antibody-escape potential of Lassa virus glycoprotein complex","authors":"","doi":"10.1016/j.immuni.2024.06.013","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.06.013","url":null,"abstract":"<p>Lassa virus is estimated to cause thousands of human deaths per year, primarily due to spillovers from its natural host, <em>Mastomys</em> rodents. Efforts to create vaccines and antibody therapeutics must account for the evolutionary variability of the Lassa virus’s glycoprotein complex (GPC), which mediates viral entry into cells and is the target of neutralizing antibodies. To map the evolutionary space accessible to GPC, we used pseudovirus deep mutational scanning to measure how nearly all GPC amino-acid mutations affected cell entry and antibody neutralization. Our experiments defined functional constraints throughout GPC. We quantified how GPC mutations affected neutralization with a panel of monoclonal antibodies. All antibodies tested were escaped by mutations that existed among natural Lassa virus lineages. Overall, our work describes a biosafety-level-2 method to elucidate the mutational space accessible to GPC and shows how prospective characterization of antigenic variation could aid the design of therapeutics and vaccines.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"26 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141618435","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}