Pub Date : 2024-03-22DOI: 10.1126/sciimmunol.adi7038
Madison S. Strine, Eric Fagerberg, Patrick W. Darcy, Gabriel M. Barrón, Renata B. Filler, Mia Madel Alfajaro, Nicole D’Angelo-Gavrish, Fang Wang, Vincent R. Graziano, Bridget L. Menasché, Martina Damo, Ya-Ting Wang, Michael R. Howitt, Sanghyun Lee, Nikhil S. Joshi, Daniel Mucida, Craig B. Wilen
The persistent murine norovirus strain MNVCR6 is a model for human norovirus and enteric viral persistence. MNVCR6 causes chronic infection by directly infecting intestinal tuft cells, rare chemosensory epithelial cells. Although MNVCR6 induces functional MNV-specific CD8+ T cells, these lymphocytes fail to clear infection. To examine how tuft cells promote immune escape, we interrogated tuft cell interactions with CD8+ T cells by adoptively transferring JEDI (just EGFP death inducing) CD8+ T cells into Gfi1b-GFP tuft cell reporter mice. Unexpectedly, some intestinal tuft cells partially resisted JEDI CD8+ T cell–mediated killing—unlike Lgr5+ intestinal stem cells and extraintestinal tuft cells—despite seemingly normal antigen presentation. When targeting intestinal tuft cells, JEDI CD8+ T cells predominantly adopted a T resident memory phenotype with decreased effector and cytotoxic capacity, enabling tuft cell survival. JEDI CD8+ T cells neither cleared nor prevented MNVCR6 infection in the colon, the site of viral persistence, despite targeting a virus-independent antigen. Ultimately, we show that intestinal tuft cells are relatively resistant to CD8+ T cells independent of norovirus infection, representing an immune-privileged niche that can be leveraged by enteric microbes.
持久性鼠诺如病毒株 MNVCR6 是人类诺如病毒和肠道病毒持久性的模型。MNVCR6 通过直接感染肠绒毛细胞（罕见的化感上皮细胞）引起慢性感染。虽然 MNVCR6 能诱导功能性 MNV 特异性 CD8+ T 细胞，但这些淋巴细胞无法清除感染。为了研究簇细胞如何促进免疫逃逸，我们通过将 JEDI（仅诱导 EGFP 死亡）CD8+ T 细胞收养性转移到 Gfi1b-GFP 簇细胞报告小鼠体内，研究了簇细胞与 CD8+ T 细胞的相互作用。意想不到的是，尽管抗原呈递看似正常，但一些肠簇细胞部分抵制了JEDI CD8+T细胞介导的杀伤--与Lgr5+肠干细胞和肠外簇细胞不同。针对肠簇细胞时，JEDI CD8+ T细胞主要采用T常驻记忆表型，效应能力和细胞毒性能力下降，从而使肠簇细胞得以存活。尽管 JEDI CD8+ T 细胞靶向的是与病毒无关的抗原，但它既不能清除也不能阻止 MNVCR6 在结肠（病毒持续存在的部位）的感染。最终，我们发现肠绒毛细胞对 CD8+ T 细胞具有相对的抵抗力，不受诺如病毒感染的影响，是肠道微生物可以利用的免疫优势位点。
{"title":"Intestinal tuft cell immune privilege enables norovirus persistence","authors":"Madison S. Strine, Eric Fagerberg, Patrick W. Darcy, Gabriel M. Barrón, Renata B. Filler, Mia Madel Alfajaro, Nicole D’Angelo-Gavrish, Fang Wang, Vincent R. Graziano, Bridget L. Menasché, Martina Damo, Ya-Ting Wang, Michael R. Howitt, Sanghyun Lee, Nikhil S. Joshi, Daniel Mucida, Craig B. Wilen","doi":"10.1126/sciimmunol.adi7038","DOIUrl":"10.1126/sciimmunol.adi7038","url":null,"abstract":"<div >The persistent murine norovirus strain MNV<sup>CR6</sup> is a model for human norovirus and enteric viral persistence. MNV<sup>CR6</sup> causes chronic infection by directly infecting intestinal tuft cells, rare chemosensory epithelial cells. Although MNV<sup>CR6</sup> induces functional MNV-specific CD8<sup>+</sup> T cells, these lymphocytes fail to clear infection. To examine how tuft cells promote immune escape, we interrogated tuft cell interactions with CD8<sup>+</sup> T cells by adoptively transferring JEDI (just EGFP death inducing) CD8<sup>+</sup> T cells into Gfi1b-GFP tuft cell reporter mice. Unexpectedly, some intestinal tuft cells partially resisted JEDI CD8<sup>+</sup> T cell–mediated killing—unlike Lgr5<sup>+</sup> intestinal stem cells and extraintestinal tuft cells—despite seemingly normal antigen presentation. When targeting intestinal tuft cells, JEDI CD8<sup>+</sup> T cells predominantly adopted a T resident memory phenotype with decreased effector and cytotoxic capacity, enabling tuft cell survival. JEDI CD8<sup>+</sup> T cells neither cleared nor prevented MNV<sup>CR6</sup> infection in the colon, the site of viral persistence, despite targeting a virus-independent antigen. Ultimately, we show that intestinal tuft cells are relatively resistant to CD8<sup>+</sup> T cells independent of norovirus infection, representing an immune-privileged niche that can be leveraged by enteric microbes.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":24.8,"publicationDate":"2024-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140190164","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 : 2024-03-22DOI: https://www.science.org/doi/10.1126/sciimmunol.adi7038
Madison S. Strine, Eric Fagerberg, Patrick W. Darcy, Gabriel M. Barrón, Renata B. Filler, Mia Madel Alfajaro, Nicole D’Angelo-Gavrish, Fang Wang, Vincent R. Graziano, Bridget L. Menasché, Martina Damo, Ya-Ting Wang, Michael R. Howitt, Sanghyun Lee, Nikhil S. Joshi, Daniel Mucida, Craig B. Wilen
The persistent murine norovirus strain MNVCR6 is a model for human norovirus and enteric viral persistence. MNVCR6 causes chronic infection by directly infecting intestinal tuft cells, rare chemosensory epithelial cells. Although MNVCR6 induces functional MNV-specific CD8+ T cells, these lymphocytes fail to clear infection. To examine how tuft cells promote immune escape, we interrogated tuft cell interactions with CD8+ T cells by adoptively transferring JEDI (just EGFP death inducing) CD8+ T cells into Gfi1b-GFP tuft cell reporter mice. Unexpectedly, some intestinal tuft cells partially resisted JEDI CD8+ T cell–mediated killing—unlike Lgr5+ intestinal stem cells and extraintestinal tuft cells—despite seemingly normal antigen presentation. When targeting intestinal tuft cells, JEDI CD8+ T cells predominantly adopted a T resident memory phenotype with decreased effector and cytotoxic capacity, enabling tuft cell survival. JEDI CD8+ T cells neither cleared nor prevented MNVCR6 infection in the colon, the site of viral persistence, despite targeting a virus-independent antigen. Ultimately, we show that intestinal tuft cells are relatively resistant to CD8+ T cells independent of norovirus infection, representing an immune-privileged niche that can be leveraged by enteric microbes.
持久性鼠诺如病毒株 MNVCR6 是人类诺如病毒和肠道病毒持久性的模型。MNVCR6 通过直接感染肠绒毛细胞（罕见的化感上皮细胞）引起慢性感染。虽然 MNVCR6 能诱导功能性 MNV 特异性 CD8+ T 细胞，但这些淋巴细胞无法清除感染。为了研究簇细胞如何促进免疫逃逸，我们通过将 JEDI（仅诱导 EGFP 死亡）CD8+ T 细胞收养性转移到 Gfi1b-GFP 簇细胞报告小鼠体内，研究了簇细胞与 CD8+ T 细胞的相互作用。意想不到的是，尽管抗原呈递看似正常，但一些肠簇细胞部分抵制了JEDI CD8+T细胞介导的杀伤--与Lgr5+肠干细胞和肠外簇细胞不同。当以肠管细胞为目标时，JEDI CD8+ T细胞主要采用T常驻记忆表型，效应能力和细胞毒性能力下降，从而使肠管细胞得以存活。尽管 JEDI CD8+ T 细胞靶向的是与病毒无关的抗原，但它既不能清除也不能阻止 MNVCR6 在结肠（病毒持续存在的部位）的感染。最终，我们发现肠绒毛细胞对 CD8+ T 细胞具有相对的抵抗力，不受诺如病毒感染的影响，是肠道微生物可以利用的免疫优势位点。
{"title":"Intestinal tuft cell immune privilege enables norovirus persistence","authors":"Madison S. Strine, Eric Fagerberg, Patrick W. Darcy, Gabriel M. Barrón, Renata B. Filler, Mia Madel Alfajaro, Nicole D’Angelo-Gavrish, Fang Wang, Vincent R. Graziano, Bridget L. Menasché, Martina Damo, Ya-Ting Wang, Michael R. Howitt, Sanghyun Lee, Nikhil S. Joshi, Daniel Mucida, Craig B. Wilen","doi":"https://www.science.org/doi/10.1126/sciimmunol.adi7038","DOIUrl":"https://doi.org/https://www.science.org/doi/10.1126/sciimmunol.adi7038","url":null,"abstract":"The persistent murine norovirus strain MNV<sup>CR6</sup> is a model for human norovirus and enteric viral persistence. MNV<sup>CR6</sup> causes chronic infection by directly infecting intestinal tuft cells, rare chemosensory epithelial cells. Although MNV<sup>CR6</sup> induces functional MNV-specific CD8<sup>+</sup> T cells, these lymphocytes fail to clear infection. To examine how tuft cells promote immune escape, we interrogated tuft cell interactions with CD8<sup>+</sup> T cells by adoptively transferring JEDI (just EGFP death inducing) CD8<sup>+</sup> T cells into Gfi1b-GFP tuft cell reporter mice. Unexpectedly, some intestinal tuft cells partially resisted JEDI CD8<sup>+</sup> T cell–mediated killing—unlike Lgr5<sup>+</sup> intestinal stem cells and extraintestinal tuft cells—despite seemingly normal antigen presentation. When targeting intestinal tuft cells, JEDI CD8<sup>+</sup> T cells predominantly adopted a T resident memory phenotype with decreased effector and cytotoxic capacity, enabling tuft cell survival. JEDI CD8<sup>+</sup> T cells neither cleared nor prevented MNV<sup>CR6</sup> infection in the colon, the site of viral persistence, despite targeting a virus-independent antigen. Ultimately, we show that intestinal tuft cells are relatively resistant to CD8<sup>+</sup> T cells independent of norovirus infection, representing an immune-privileged niche that can be leveraged by enteric microbes.","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":24.8,"publicationDate":"2024-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140192599","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 : 2024-03-22DOI: https://www.science.org/doi/10.1126/sciimmunol.adi8150
Theo van den Broek, Kristine Oleinika, Siti Rahmayanti, Carlos Castrillon, Cees E. van der Poel, Michael C. Carroll
In autoreactive germinal centers (GC) initiated by a single rogue B cell clone, wild-type B cells expand and give rise to clones that target other autoantigens, known as epitope spreading. The chronic, progressive nature of epitope spreading calls for early interventions to limit autoimmune pathologies, but the kinetics and molecular requirements for wild-type B cell invasion and participation in GC remain largely unknown. With parabiosis and adoptive transfer approaches in a murine model of systemic lupus erythematosus, we demonstrate that wild-type B cells join existing GCs rapidly, clonally expand, persist, and contribute to autoantibody production and diversification. The invasion of autoreactive GCs by wild-type B cells required TLR7, B cell receptor specificity, antigen presentation, and type I interferon signaling. The adoptive transfer model provides a tool for identifying early events in the breaking of B cell tolerance in autoimmunity.
在由单个不听话的 B 细胞克隆引发的自身反应性生殖中心（GC）中，野生型 B 细胞会扩张并产生以其他自身抗原为靶点的克隆，这就是所谓的表位扩散。表位扩散的慢性、进行性特点要求早期干预以限制自身免疫性病变，但野生型 B 细胞入侵和参与 GC 的动力学和分子要求在很大程度上仍是未知的。通过在系统性红斑狼疮小鼠模型中采用同种异体移植和收养性转移方法，我们证明了野生型 B 细胞能迅速加入现有的 GC，进行克隆扩增、持续存在，并促进自身抗体的产生和多样化。野生型 B 细胞入侵自体反应性 GC 需要 TLR7、B 细胞受体特异性、抗原递呈和 I 型干扰素信号传导。收养性转移模型为确定自身免疫中B细胞耐受性破坏的早期事件提供了一种工具。
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Pub Date : 2024-03-22DOI: 10.1126/sciimmunol.adj9534
Ivan Kosik, Jefferson Da Silva Santos, Mathew Angel, Zhe Hu, Jaroslav Holly, James S. Gibbs, Tanner Gill, Martina Kosikova, Tiansheng Li, William Bakhache, Patrick T. Dolan, Hang Xie, Sarah F. Andrews, Rebecca A. Gillespie, Masaru Kanekiyo, Adrian B. McDermott, Theodore C. Pierson, Jonathan W. Yewdell
Antigenic drift, the gradual accumulation of amino acid substitutions in the influenza virus hemagglutinin (HA) receptor protein, enables viral immune evasion. Antibodies (Abs) specific for the drift-resistant HA stem region are a promising universal influenza vaccine target. Although anti-stem Abs are not believed to block viral attachment, here we show that complement component 1q (C1q), a 460-kilodalton protein with six Ab Fc-binding domains, confers attachment inhibition to anti-stem Abs and enhances their fusion and neuraminidase inhibition. As a result, virus neutralization activity in vitro is boosted up to 30-fold, and in vivo protection from influenza PR8 infection in mice is enhanced. These effects reflect increased steric hindrance and not increased Ab avidity. C1q greatly expands the anti-stem Ab viral escape repertoire to include residues throughout the HA, some of which cause antigenic alterations in the globular region or modulate HA receptor avidity. We also show that C1q enhances the neutralization activity of non–receptor binding domain anti–SARS-CoV-2 spike Abs, an effect dependent on spike density on the virion surface. These findings demonstrate that C1q can greatly expand Ab function and thereby contribute to viral evolution and immune escape.
抗原漂移是流感病毒血凝素（HA）受体蛋白中氨基酸替代的逐渐积累，它使病毒能够逃避免疫。抗漂移的 HA 茎部特异性抗体（Abs）是一种很有前景的通用流感疫苗靶标。尽管人们认为抗干抗体不会阻断病毒附着，但我们在此发现，补体成分 1q（C1q）是一种具有六个抗体 Fc 结合域的 460 千道尔顿蛋白，它能抑制抗干抗体的附着，并增强其融合和神经氨酸酶抑制作用。因此，体外病毒中和活性可提高 30 倍，小鼠体内免受 PR8 流感感染的保护能力也得到增强。这些效果反映的是立体阻碍的增加，而不是抗体亲和力的提高。C1q 大大扩展了抗干体抗体病毒逃逸库，使其包括整个 HA 的残基，其中一些残基会导致球状区的抗原性改变或调节 HA 受体的嗜性。我们还发现，C1q 能增强非受体结合域抗 SARS-CoV-2 尖峰抗体的中和活性，这种效应取决于病毒表面的尖峰密度。这些研究结果表明，C1q 可以大大扩展抗体的功能，从而促进病毒进化和免疫逃逸。
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Pub Date : 2024-03-22DOI: 10.1126/sciimmunol.adi8150
Theo van den Broek, Kristine Oleinika, Siti Rahmayanti, Carlos Castrillon, Cees E. van der Poel, Michael C. Carroll
In autoreactive germinal centers (GC) initiated by a single rogue B cell clone, wild-type B cells expand and give rise to clones that target other autoantigens, known as epitope spreading. The chronic, progressive nature of epitope spreading calls for early interventions to limit autoimmune pathologies, but the kinetics and molecular requirements for wild-type B cell invasion and participation in GC remain largely unknown. With parabiosis and adoptive transfer approaches in a murine model of systemic lupus erythematosus, we demonstrate that wild-type B cells join existing GCs rapidly, clonally expand, persist, and contribute to autoantibody production and diversification. The invasion of autoreactive GCs by wild-type B cells required TLR7, B cell receptor specificity, antigen presentation, and type I interferon signaling. The adoptive transfer model provides a tool for identifying early events in the breaking of B cell tolerance in autoimmunity.
在由单个不听话的 B 细胞克隆引发的自身反应性生殖中心（GC）中，野生型 B 细胞会扩张并产生以其他自身抗原为靶点的克隆，这就是所谓的表位扩散。表位扩散的慢性、进行性特点要求早期干预以限制自身免疫性病变，但野生型 B 细胞入侵和参与 GC 的动力学和分子要求在很大程度上仍是未知的。通过在系统性红斑狼疮小鼠模型中采用同种异体移植和收养性转移方法，我们证明了野生型 B 细胞能迅速加入现有的 GC，进行克隆扩增、持续存在，并促进自身抗体的产生和多样化。野生型 B 细胞入侵自体反应性 GC 需要 TLR7、B 细胞受体特异性、抗原递呈和 I 型干扰素信号传导。收养性转移模型为确定自身免疫中B细胞耐受性破坏的早期事件提供了一种工具。
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Pub Date : 2024-03-15DOI: 10.1126/sciimmunol.adj4775
Katherine Z. Sanidad, Stephanie L. Rager, Hannah C. Carrow, Aparna Ananthanarayanan, Ryann Callaghan, Lucy R. Hart, Tingting Li, Purnima Ravisankar, Julia A. Brown, Mohammed Amir, Jenny C. Jin, Alexandria Rose Savage, Ryan Luo, Florencia Mardorsky Rowdo, M. Laura Martin, Randi B. Silver, Chun-Jun Guo, Jan Krumsiek, Naohiro Inohara, Melody Y. Zeng
The gut microbiota promotes immune system development in early life, but the interactions between the gut metabolome and immune cells in the neonatal gut remain largely undefined. Here, we demonstrate that the neonatal gut is uniquely enriched with neurotransmitters, including serotonin, and that specific gut bacteria directly produce serotonin while down-regulating monoamine oxidase A to limit serotonin breakdown. We found that serotonin directly signals to T cells to increase intracellular indole-3-acetaldehdye and inhibit mTOR activation, thereby promoting the differentiation of regulatory T cells, both ex vivo and in vivo in the neonatal intestine. Oral gavage of serotonin into neonatal mice resulted in long-term T cell–mediated antigen-specific immune tolerance toward both dietary antigens and commensal bacteria. Together, our study has uncovered an important role for specific gut bacteria to increase serotonin availability in the neonatal gut and identified a function of gut serotonin in shaping T cell response to dietary antigens and commensal bacteria to promote immune tolerance in early life.
肠道微生物群促进生命早期免疫系统的发育，但新生儿肠道代谢组和免疫细胞之间的相互作用在很大程度上仍未确定。在这里，我们证明了新生儿肠道独特地富含包括血清素在内的神经递质，特定的肠道细菌直接产生血清素，同时下调单胺氧化酶 A 以限制血清素的分解。我们发现，5-羟色胺直接向T细胞发出信号，增加细胞内吲哚-3-乙酰胆碱染料，抑制mTOR的激活，从而促进调节性T细胞的分化。给新生小鼠口服羟色胺可导致T细胞介导的对饮食抗原和共生细菌的长期抗原特异性免疫耐受。总之，我们的研究揭示了特定肠道细菌在增加新生儿肠道血清素可用性方面的重要作用，并确定了肠道血清素在塑造 T 细胞对饮食抗原和共生细菌的反应以促进生命早期免疫耐受方面的功能。
{"title":"Gut bacteria–derived serotonin promotes immune tolerance in early life","authors":"Katherine Z. Sanidad, Stephanie L. Rager, Hannah C. Carrow, Aparna Ananthanarayanan, Ryann Callaghan, Lucy R. Hart, Tingting Li, Purnima Ravisankar, Julia A. Brown, Mohammed Amir, Jenny C. Jin, Alexandria Rose Savage, Ryan Luo, Florencia Mardorsky Rowdo, M. Laura Martin, Randi B. Silver, Chun-Jun Guo, Jan Krumsiek, Naohiro Inohara, Melody Y. Zeng","doi":"10.1126/sciimmunol.adj4775","DOIUrl":"10.1126/sciimmunol.adj4775","url":null,"abstract":"<div >The gut microbiota promotes immune system development in early life, but the interactions between the gut metabolome and immune cells in the neonatal gut remain largely undefined. Here, we demonstrate that the neonatal gut is uniquely enriched with neurotransmitters, including serotonin, and that specific gut bacteria directly produce serotonin while down-regulating monoamine oxidase A to limit serotonin breakdown. We found that serotonin directly signals to T cells to increase intracellular indole-3-acetaldehdye and inhibit mTOR activation, thereby promoting the differentiation of regulatory T cells, both ex vivo and in vivo in the neonatal intestine. Oral gavage of serotonin into neonatal mice resulted in long-term T cell–mediated antigen-specific immune tolerance toward both dietary antigens and commensal bacteria. Together, our study has uncovered an important role for specific gut bacteria to increase serotonin availability in the neonatal gut and identified a function of gut serotonin in shaping T cell response to dietary antigens and commensal bacteria to promote immune tolerance in early life.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":24.8,"publicationDate":"2024-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adj4775","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140137226","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-15DOI: https://www.science.org/doi/10.1126/sciimmunol.adn4958
Veera Panova, Arianne C. Richard
Upon lymphocyte stimulation, accumulation of intracellular NAD(H) reflects the strength of antigen receptor signals and controls the rate of cell cycle entry and proliferation (see related Research Article by Turner et al.).
{"title":"A metabolic pacer ensures smooth running of the lymphocyte activation race","authors":"Veera Panova, Arianne C. Richard","doi":"https://www.science.org/doi/10.1126/sciimmunol.adn4958","DOIUrl":"https://doi.org/https://www.science.org/doi/10.1126/sciimmunol.adn4958","url":null,"abstract":"Upon lymphocyte stimulation, accumulation of intracellular NAD(H) reflects the strength of antigen receptor signals and controls the rate of cell cycle entry and proliferation (see related Research Article by Turner <i>et al</i>.).","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":24.8,"publicationDate":"2024-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140139359","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 : 2024-03-15DOI: https://www.science.org/doi/10.1126/sciimmunol.adh5318
Abani Kanta Naik, Danielle J. Dauphars, Elizabeth Corbett, Lunden Simpson, David G. Schatz, Michael S. Krangel
Recombination activating gene (RAG) expression increases as thymocytes transition from the CD4−CD8− double-negative (DN) to the CD4+CD8+ double-positive (DP) stage, but the physiological importance and mechanism of transcriptional up-regulation are unknown. Here, we show that a DP-specific component of the recombination activating genes antisilencer (DPASE) provokes elevated RAG expression in DP thymocytes. Mouse DP thymocytes lacking the DPASE display RAG expression equivalent to that in DN thymocytes, but this supports only a partial Tcra repertoire due to inefficient secondary Vα-Jα rearrangement. These data indicate that RAG up-regulation is required for a replete Tcra repertoire and that RAG expression is fine-tuned during lymphocyte development to meet the requirements of distinct antigen receptor loci. We further show that transcription factor RORγt directs RAG up-regulation in DP thymocytes by binding to the DPASE and that RORγt influences the Tcra repertoire by binding to the Tcra enhancer. These data, together with prior work showing RORγt to control Tcra rearrangement by regulating DP thymocyte proliferation and survival, reveal RORγt to orchestrate multiple pathways that support formation of the Tcra repertoire.
{"title":"RORγt up-regulates RAG gene expression in DP thymocytes to expand the Tcra repertoire","authors":"Abani Kanta Naik, Danielle J. Dauphars, Elizabeth Corbett, Lunden Simpson, David G. Schatz, Michael S. Krangel","doi":"https://www.science.org/doi/10.1126/sciimmunol.adh5318","DOIUrl":"https://doi.org/https://www.science.org/doi/10.1126/sciimmunol.adh5318","url":null,"abstract":"Recombination activating gene (RAG) expression increases as thymocytes transition from the CD4<sup>−</sup>CD8<sup>−</sup> double-negative (DN) to the CD4<sup>+</sup>CD8<sup>+</sup> double-positive (DP) stage, but the physiological importance and mechanism of transcriptional up-regulation are unknown. Here, we show that a DP-specific component of the recombination activating genes antisilencer (DPASE) provokes elevated RAG expression in DP thymocytes. Mouse DP thymocytes lacking the DPASE display RAG expression equivalent to that in DN thymocytes, but this supports only a partial <i>Tcra</i> repertoire due to inefficient secondary Vα-Jα rearrangement. These data indicate that RAG up-regulation is required for a replete <i>Tcra</i> repertoire and that RAG expression is fine-tuned during lymphocyte development to meet the requirements of distinct antigen receptor loci. We further show that transcription factor RORγt directs RAG up-regulation in DP thymocytes by binding to the DPASE and that RORγt influences the <i>Tcra</i> repertoire by binding to the <i>Tcra</i> enhancer. These data, together with prior work showing RORγt to control <i>Tcra</i> rearrangement by regulating DP thymocyte proliferation and survival, reveal RORγt to orchestrate multiple pathways that support formation of the <i>Tcra</i> repertoire.","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":24.8,"publicationDate":"2024-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140161955","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 : 2024-03-15DOI: 10.1126/sciimmunol.adj7238
Lucien Turner, Tran Ngoc Van Le, Eric Cross, Clemence Queriault, Montana Knight, Krittin Trihemasava, James Davis, Patrick Schaefer, Janet Nguyen, Jimmy Xu, Brian Goldspiel, Elise Hall, Kelly Rome, Michael Scaglione, Joel Eggert, Byron Au-Yeung, Douglas C. Wallace, Clementina Mesaros, Joseph A. Baur, Will Bailis
Adaptive immunity requires the expansion of high-affinity lymphocytes from a heterogeneous pool. Whereas current models explain this through signal transduction, we hypothesized that antigen affinity tunes discrete metabolic pathways to license clonal lymphocyte dynamics. Here, we identify nicotinamide adenine dinucleotide (NAD) biosynthesis as a biochemical hub for the T cell receptor affinity–dependent metabolome. Through this central anabolic role, we found that NAD biosynthesis governs a quiescence exit checkpoint, thereby pacing proliferation. Normalizing cellular NAD(H) likewise normalizes proliferation across affinities, and enhancing NAD biosynthesis permits the expansion of lower affinity clones. Furthermore, single-cell differences in NAD(H) could predict division potential for both T and B cells, before the first division, unmixing proliferative heterogeneity. We believe that this supports a broader paradigm in which complex signaling networks converge on metabolic pathways to control single-cell behavior.
适应性免疫需要高亲和力淋巴细胞从异质库中扩增。目前的模型是通过信号转导来解释这一点的，而我们则假设抗原亲和力会调节离散的代谢途径，从而许可克隆淋巴细胞的动态变化。在这里，我们发现烟酰胺腺嘌呤二核苷酸（NAD）的生物合成是 T 细胞受体亲和力依赖性代谢组的生化枢纽。通过这一核心合成代谢作用，我们发现 NAD 生物合成可控制静止退出检查点，从而为增殖提供节奏。使细胞中的 NAD（H）正常化同样也能使不同亲和力的增殖正常化，而增强 NAD 的生物合成则能使低亲和力克隆扩大。此外，NAD(H)的单细胞差异可以预测T细胞和B细胞在第一次分裂前的分裂潜力，从而消除增殖异质性。我们认为，这支持了一种更广泛的范式，即复杂的信号网络汇聚到代谢途径上，从而控制单细胞的行为。
{"title":"Single-cell NAD(H) levels predict clonal lymphocyte expansion dynamics","authors":"Lucien Turner, Tran Ngoc Van Le, Eric Cross, Clemence Queriault, Montana Knight, Krittin Trihemasava, James Davis, Patrick Schaefer, Janet Nguyen, Jimmy Xu, Brian Goldspiel, Elise Hall, Kelly Rome, Michael Scaglione, Joel Eggert, Byron Au-Yeung, Douglas C. Wallace, Clementina Mesaros, Joseph A. Baur, Will Bailis","doi":"10.1126/sciimmunol.adj7238","DOIUrl":"10.1126/sciimmunol.adj7238","url":null,"abstract":"<div >Adaptive immunity requires the expansion of high-affinity lymphocytes from a heterogeneous pool. Whereas current models explain this through signal transduction, we hypothesized that antigen affinity tunes discrete metabolic pathways to license clonal lymphocyte dynamics. Here, we identify nicotinamide adenine dinucleotide (NAD) biosynthesis as a biochemical hub for the T cell receptor affinity–dependent metabolome. Through this central anabolic role, we found that NAD biosynthesis governs a quiescence exit checkpoint, thereby pacing proliferation. Normalizing cellular NAD(H) likewise normalizes proliferation across affinities, and enhancing NAD biosynthesis permits the expansion of lower affinity clones. Furthermore, single-cell differences in NAD(H) could predict division potential for both T and B cells, before the first division, unmixing proliferative heterogeneity. We believe that this supports a broader paradigm in which complex signaling networks converge on metabolic pathways to control single-cell behavior.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":24.8,"publicationDate":"2024-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adj7238","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140137228","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-15DOI: 10.1126/sciimmunol.adn4958
Veera Panova, Arianne C. Richard
Upon lymphocyte stimulation, accumulation of intracellular NAD(H) reflects the strength of antigen receptor signals and controls the rate of cell cycle entry and proliferation (see related Research Article by Turner et al.).
{"title":"A metabolic pacer ensures smooth running of the lymphocyte activation race","authors":"Veera Panova, Arianne C. Richard","doi":"10.1126/sciimmunol.adn4958","DOIUrl":"10.1126/sciimmunol.adn4958","url":null,"abstract":"<div >Upon lymphocyte stimulation, accumulation of intracellular NAD(H) reflects the strength of antigen receptor signals and controls the rate of cell cycle entry and proliferation (see related Research Article by Turner <i>et al</i>.).</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":24.8,"publicationDate":"2024-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adn4958","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140137225","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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