Pub Date : 2025-01-03DOI: 10.1016/j.immuni.2024.12.004
Julien Champagne, Morten M. Nielsen, Xiaodong Feng, Jasmine Montenegro Navarro, Abhijeet Pataskar, Rhianne Voogd, Lisanne Giebel, Remco Nagel, Nadine Berenst, Amos Fumagalli, Adva Kochavi, Domenica Lovecchio, Lorenzo Valcanover, Yuval Malka, Weiwen Yang, Maarja Laos, Yingqian Li, Natalie Proost, Marieke van de Ven, Olaf van Tellingen, Reuven Agami
Prolonged exposure to interferon-gamma (IFNγ) and the associated increased expression of the enzyme indoleamine 2,3-dioxygenase 1 (IDO1) create an intracellular shortage of tryptophan in the cancer cells, which stimulates ribosomal frameshifting and tryptophan to phenylalanine (W>F) codon reassignments during protein synthesis. Here, we investigated whether such neoepitopes can be useful targets of adoptive T cell therapy. Immunopeptidomic analyses uncovered hundreds of W>F neoepitopes mainly presented by the HLA-A∗24:02 allele. We identified a T cell receptor (TCRTMBIM6W>F.1) possessing high affinity and specificity toward TMBIM6W>F/HLA-A∗24:02, the inducible W>F neoepitope with the broadest expression across cancer cell lines. TCRTMBIM6W>F.1 T cells are activated by tryptophan-depleted cancer cells but not by non-cancer cells. Finally, we provide in vivo proof of concept for clinical application, whereby TCRMART1 T cells promote cancer cell killing by TCRTMBIM6W>F.1 T cells through the generation of W>F neoepitopes. Thus, neoepitopes arising from W>F substitution present shared and highly expressed immunogenic targets with the potential to overcome current limitations in adoptive T cell therapy.
{"title":"Adoptive T cell therapy targeting an inducible and broadly shared product of aberrant mRNA translation","authors":"Julien Champagne, Morten M. Nielsen, Xiaodong Feng, Jasmine Montenegro Navarro, Abhijeet Pataskar, Rhianne Voogd, Lisanne Giebel, Remco Nagel, Nadine Berenst, Amos Fumagalli, Adva Kochavi, Domenica Lovecchio, Lorenzo Valcanover, Yuval Malka, Weiwen Yang, Maarja Laos, Yingqian Li, Natalie Proost, Marieke van de Ven, Olaf van Tellingen, Reuven Agami","doi":"10.1016/j.immuni.2024.12.004","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.12.004","url":null,"abstract":"Prolonged exposure to interferon-gamma (IFNγ) and the associated increased expression of the enzyme indoleamine 2,3-dioxygenase 1 (IDO1) create an intracellular shortage of tryptophan in the cancer cells, which stimulates ribosomal frameshifting and tryptophan to phenylalanine (W>F) codon reassignments during protein synthesis. Here, we investigated whether such neoepitopes can be useful targets of adoptive T cell therapy. Immunopeptidomic analyses uncovered hundreds of W>F neoepitopes mainly presented by the HLA-A<sup>∗</sup>24:02 allele. We identified a T cell receptor (TCR<sup>TMBIM6W>F.1</sup>) possessing high affinity and specificity toward TMBIM6<sup>W>F</sup>/HLA-A<sup>∗</sup>24:02, the inducible W>F neoepitope with the broadest expression across cancer cell lines. TCR<sup>TMBIM6W>F.1</sup> T cells are activated by tryptophan-depleted cancer cells but not by non-cancer cells. Finally, we provide <em>in vivo</em> proof of concept for clinical application, whereby TCR<sup>MART1</sup> T cells promote cancer cell killing by TCR<sup>TMBIM6W>F.1</sup> T cells through the generation of W>F neoepitopes. Thus, neoepitopes arising from W>F substitution present shared and highly expressed immunogenic targets with the potential to overcome current limitations in adoptive T cell therapy.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"14 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142917896","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 : 2024-12-31DOI: 10.1016/j.immuni.2024.12.006
Thumbi Ndung’u, Johanna A. Joyce, Chuan Wu, Miriam Merad, Gabriel A. Rabinovich, Jamie Rossjohn, Muzlifah Haniffa, Stephen C. Jameson
There are many dimensions to scientific life. We asked investigators about the impact of service to the scientific community and beyond and how service has shaped their experience, perspective, and research path.
{"title":"Service","authors":"Thumbi Ndung’u, Johanna A. Joyce, Chuan Wu, Miriam Merad, Gabriel A. Rabinovich, Jamie Rossjohn, Muzlifah Haniffa, Stephen C. Jameson","doi":"10.1016/j.immuni.2024.12.006","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.12.006","url":null,"abstract":"There are many dimensions to scientific life. We asked investigators about the impact of service to the scientific community and beyond and how service has shaped their experience, perspective, and research path.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"97 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142905120","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 : 2024-12-27DOI: 10.1016/j.immuni.2024.12.003
Anneka Allman, Brian T. Gaudette, Samantha Kelly, Nagham Alouche, Léolène J. Carrington, Eric Perkey, Joshua D. Brandstadter, Riley Outen, Ashley Vanderbeck, Katlyn Lederer, Yeqiao Zhou, Robert B. Faryabi, Tanner F. Robertson, Janis K. Burkhardt, Anastasia Tikhonova, Iannis Aifantis, Leonardo Scarpellino, Ute Koch, Freddy Radtke, Mechthild Lütge, Ivan Maillard
Innate-like splenic marginal zone (MZ) B (MZB) cells play unique roles in immunity due to their rapid responsiveness to blood-borne microbes. How MZB cells integrate cell-extrinsic and -intrinsic processes to achieve accelerated responsiveness is unclear. We found that Delta-like1 (Dll1) Notch ligands in splenic fibroblasts regulated MZB cell pool size, migration, and function. Dll1 could not be replaced by the alternative Notch ligand Dll4. Dll1-Notch2 signaling regulated a Myc-dependent gene expression program fostering cell growth and a Myc-independent program controlling cell-movement regulators such as sphingosine-1 phosphate receptor 1 (S1PR1). S1pr1-deficient B cells experienced Notch signaling within B cell follicles without entering the MZ and were retained in the spleen upon Notch deprivation. Key elements of the mouse B cell Notch regulome were preserved in subsets of human memory B cells and B cell lymphomas. Thus, specialized niches program the poised state and patrolling behavior of MZB cells via conserved Myc-dependent and Myc-independent Notch2-regulated mechanisms.
{"title":"Splenic fibroblasts control marginal zone B cell movement and function via two distinct Notch2-dependent regulatory programs","authors":"Anneka Allman, Brian T. Gaudette, Samantha Kelly, Nagham Alouche, Léolène J. Carrington, Eric Perkey, Joshua D. Brandstadter, Riley Outen, Ashley Vanderbeck, Katlyn Lederer, Yeqiao Zhou, Robert B. Faryabi, Tanner F. Robertson, Janis K. Burkhardt, Anastasia Tikhonova, Iannis Aifantis, Leonardo Scarpellino, Ute Koch, Freddy Radtke, Mechthild Lütge, Ivan Maillard","doi":"10.1016/j.immuni.2024.12.003","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.12.003","url":null,"abstract":"Innate-like splenic marginal zone (MZ) B (MZB) cells play unique roles in immunity due to their rapid responsiveness to blood-borne microbes. How MZB cells integrate cell-extrinsic and -intrinsic processes to achieve accelerated responsiveness is unclear. We found that Delta-like1 (Dll1) Notch ligands in splenic fibroblasts regulated MZB cell pool size, migration, and function. Dll1 could not be replaced by the alternative Notch ligand Dll4. Dll1-Notch2 signaling regulated a Myc-dependent gene expression program fostering cell growth and a Myc-independent program controlling cell-movement regulators such as sphingosine-1 phosphate receptor 1 (S1PR1). S1pr1-deficient B cells experienced Notch signaling within B cell follicles without entering the MZ and were retained in the spleen upon Notch deprivation. Key elements of the mouse B cell Notch regulome were preserved in subsets of human memory B cells and B cell lymphomas. Thus, specialized niches program the poised state and patrolling behavior of MZB cells via conserved Myc-dependent and Myc-independent Notch2-regulated mechanisms.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"32 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142887517","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 : 2024-12-27DOI: 10.1016/j.immuni.2024.11.025
Brooke D. Huisman, Daniel A. Michelson, Sara A. Rubin, Katherine Kohlsaat, Wilson Gomarga, Yuan Fang, Ji Myung Lee, Pedro del Nido, Meena Nathan, Christophe Benoist, Leonard Zon, Diane Mathis
Thymic mimetic cells are molecular hybrids between medullary-thymic-epithelial cells (mTECs) and diverse peripheral cell types. They are involved in eliminating autoreactive T cells and can perform supplementary functions reflective of their peripheral-cell counterparts. Current knowledge about mimetic cells derives largely from mouse models. To provide the high resolution that proved revelatory for mice, we performed single-cell RNA sequencing on purified mimetic-cell compartments from human pediatric donors. The single-cell profiles of individual donors were surprisingly similar, with diversification of neuroendocrine subtypes and expansion of the muscle subtype relative to mice. Informatic and imaging studies on the muscle-mTEC population highlighted a maturation trajectory suggestive of skeletal-muscle differentiation, some striated structures, and occasional cellular groupings reminiscent of neuromuscular junctions. We also profiled thymic mimetic cells from zebrafish. Integration of data from the three species identified species-specific adaptations but substantial interspecies conservation, highlighting the evolutionarily ancient nature of mimetic mTECs. Our findings provide a landscape view of human mimetic cells, with anticipated relevance in autoimmunity.
{"title":"Cross-species analyses of thymic mimetic cells reveal evolutionarily ancient origins and both conserved and species-specific elements","authors":"Brooke D. Huisman, Daniel A. Michelson, Sara A. Rubin, Katherine Kohlsaat, Wilson Gomarga, Yuan Fang, Ji Myung Lee, Pedro del Nido, Meena Nathan, Christophe Benoist, Leonard Zon, Diane Mathis","doi":"10.1016/j.immuni.2024.11.025","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.11.025","url":null,"abstract":"Thymic mimetic cells are molecular hybrids between medullary-thymic-epithelial cells (mTECs) and diverse peripheral cell types. They are involved in eliminating autoreactive T cells and can perform supplementary functions reflective of their peripheral-cell counterparts. Current knowledge about mimetic cells derives largely from mouse models. To provide the high resolution that proved revelatory for mice, we performed single-cell RNA sequencing on purified mimetic-cell compartments from human pediatric donors. The single-cell profiles of individual donors were surprisingly similar, with diversification of neuroendocrine subtypes and expansion of the muscle subtype relative to mice. Informatic and imaging studies on the muscle-mTEC population highlighted a maturation trajectory suggestive of skeletal-muscle differentiation, some striated structures, and occasional cellular groupings reminiscent of neuromuscular junctions. We also profiled thymic mimetic cells from zebrafish. Integration of data from the three species identified species-specific adaptations but substantial interspecies conservation, highlighting the evolutionarily ancient nature of mimetic mTECs. Our findings provide a landscape view of human mimetic cells, with anticipated relevance in autoimmunity.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"41 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142887518","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 : 2024-12-26DOI: 10.1016/j.immuni.2024.11.023
Carina Diehl, Valeria Soberón, Seren Baygün, Yuanyan Chu, Jonathan Mandelbaum, Laura Kraus, Thomas Engleitner, Martina Rudelius, Marco Fangazio, Christoph Daniel, Sabrina Bortoluzzi, Sabine Helmrath, Pankaj Singroul, Vanessa Gölling, Francisco Osorio Barrios, Gönül Seyhan, Lena Oßwald, Maike Kober-Hasslacher, Theodor Zeng, Rupert Öllinger, Marc Schmidt-Supprian
B cell immunity carries the inherent risk of deviating into autoimmunity and malignancy, which are both strongly associated with genetic variants or alterations that increase immune signaling. Here, we investigated the interplay of autoimmunity and lymphoma risk factors centered around the archetypal negative immune regulator TNFAIP3/A20 in mice. Counterintuitively, B cells with moderately elevated sensitivity to stimulation caused fatal autoimmune pathology, while those with high sensitivity did not. We resolved this apparent paradox by identifying a rheostat-like cytotoxic T cell checkpoint. Cytotoxicity was instructed by and directed against B cells with high intrinsic hyperresponsiveness, while less reactive cells were spared. Removing T cell control restored a linear relationship between intrinsic B cell reactivity and lethal lymphoproliferation, lymphomagenesis, and autoinflammation. We thus identify powerful T cell-mediated negative feedback control of inherited and acquired B cell pathogenicity and define a permissive window for autoimmunity to emerge.
{"title":"Hyperreactive B cells instruct their elimination by T cells to curb autoinflammation and lymphomagenesis","authors":"Carina Diehl, Valeria Soberón, Seren Baygün, Yuanyan Chu, Jonathan Mandelbaum, Laura Kraus, Thomas Engleitner, Martina Rudelius, Marco Fangazio, Christoph Daniel, Sabrina Bortoluzzi, Sabine Helmrath, Pankaj Singroul, Vanessa Gölling, Francisco Osorio Barrios, Gönül Seyhan, Lena Oßwald, Maike Kober-Hasslacher, Theodor Zeng, Rupert Öllinger, Marc Schmidt-Supprian","doi":"10.1016/j.immuni.2024.11.023","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.11.023","url":null,"abstract":"B cell immunity carries the inherent risk of deviating into autoimmunity and malignancy, which are both strongly associated with genetic variants or alterations that increase immune signaling. Here, we investigated the interplay of autoimmunity and lymphoma risk factors centered around the archetypal negative immune regulator <em>TNFAIP3</em>/A20 in mice. Counterintuitively, B cells with moderately elevated sensitivity to stimulation caused fatal autoimmune pathology, while those with high sensitivity did not. We resolved this apparent paradox by identifying a rheostat-like cytotoxic T cell checkpoint. Cytotoxicity was instructed by and directed against B cells with high intrinsic hyperresponsiveness, while less reactive cells were spared. Removing T cell control restored a linear relationship between intrinsic B cell reactivity and lethal lymphoproliferation, lymphomagenesis, and autoinflammation. We thus identify powerful T cell-mediated negative feedback control of inherited and acquired B cell pathogenicity and define a permissive window for autoimmunity to emerge.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"62 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142886878","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 : 2024-12-25DOI: 10.1016/j.immuni.2024.11.026
Jessica Waibl Polania, Alexandra Hoyt-Miggelbrink, William H. Tomaszewski, Lucas P. Wachsmuth, Selena J. Lorrey, Daniel S. Wilkinson, Emily Lerner, Karolina Woroniecka, John B. Finlay, Katayoun Ayasoufi, Peter E. Fecci
Whereas terminally exhausted T (Tex_term) cells retain anti-tumor cytotoxic functions, the frequencies of stem-like progenitor-exhausted T (Tex_prog) cells better reflect immunotherapeutic responsivity. Here, we examined the intratumoral cellular interactions that govern the transition to terminal T cell exhaustion. We defined a metric reflecting the intratumoral progenitor exhaustion-to-terminal exhaustion ratio (PETER), which decreased with tumor progression in solid cancers. Single-cell analyses of Tex_prog cells and Tex_term cells in glioblastoma (GBM), a setting of severe T cell exhaustion, revealed disproportionate loss of Tex_prog cells over time. Exhaustion concentrated within tumor-specific T cell subsets, with cognate antigen exposure requisite for acquisition of the Tex_term phenotype. Tumor-associated macrophages (TAMs)—not tumor cells—were the primary source of antigenic exposure governing the Tex_prog to Tex_term transition. TAM depletion increased frequencies of Tex_prog cells in multiple tumor models, increased PETER, and promoted responsiveness to αPD1 immunotherapy. Thus, targeting TAM-T cell interactions may further license checkpoint blockade responses.
{"title":"Antigen presentation by tumor-associated macrophages drives T cells from a progenitor exhaustion state to terminal exhaustion","authors":"Jessica Waibl Polania, Alexandra Hoyt-Miggelbrink, William H. Tomaszewski, Lucas P. Wachsmuth, Selena J. Lorrey, Daniel S. Wilkinson, Emily Lerner, Karolina Woroniecka, John B. Finlay, Katayoun Ayasoufi, Peter E. Fecci","doi":"10.1016/j.immuni.2024.11.026","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.11.026","url":null,"abstract":"Whereas terminally exhausted T (Tex_term) cells retain anti-tumor cytotoxic functions, the frequencies of stem-like progenitor-exhausted T (Tex_prog) cells better reflect immunotherapeutic responsivity. Here, we examined the intratumoral cellular interactions that govern the transition to terminal T cell exhaustion. We defined a metric reflecting the intratumoral progenitor exhaustion-to-terminal exhaustion ratio (PETER), which decreased with tumor progression in solid cancers. Single-cell analyses of Tex_prog cells and Tex_term cells in glioblastoma (GBM), a setting of severe T cell exhaustion, revealed disproportionate loss of Tex_prog cells over time. Exhaustion concentrated within tumor-specific T cell subsets, with cognate antigen exposure requisite for acquisition of the Tex_term phenotype. Tumor-associated macrophages (TAMs)—not tumor cells—were the primary source of antigenic exposure governing the Tex_prog to Tex_term transition. TAM depletion increased frequencies of Tex_prog cells in multiple tumor models, increased PETER, and promoted responsiveness to αPD1 immunotherapy. Thus, targeting TAM-T cell interactions may further license checkpoint blockade responses.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"53 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142884076","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 : 2024-12-23DOI: 10.1016/j.immuni.2024.11.021
Anna Lena Kastner, Anna-Friederike Marx, Mirela Dimitrova, Tiago Abreu-Mota, Yusuf I. Ertuna, Weldy V. Bonilla, Karsten Stauffer, Marco Künzli, Ingrid Wagner, Mario Kreutzfeldt, Doron Merkler, Daniel D. Pinschewer
To interrogate the role of specific immune cells in infection, cancer, and autoimmunity, immunologists commonly use monoclonal depletion antibodies (depletion-mAbs) or genetically engineered mouse models (GEMMs). To generate a tool that combines specific advantages and avoids select drawbacks of the two methods, we engineered adeno-associated viral vectors expressing depletion mAbs (depletion-AAVs). Single-dose depletion-AAV administration durably eliminated lymphocyte subsets in mice and avoided accessory deficiencies of GEMMs, such as marginal zone defects in B cell-deficient animals. Depletion-AAVs can be used in animals of different genetic backgrounds, and multiple depletion-AAVs can readily be combined. Exploiting depletion-AAV technology, we showed that B cells were required for unimpaired CD4+ and CD8+ T cell responses to chronic lymphocytic choriomeningitis virus (LCMV) infection. Upon B cell depletion, CD8+ T cells failed to suppress viremia, and they only helped resolve chronic infection when antibodies dampened viral loads. Our study positions depletion-AAVs as a versatile tool for immunological research.
{"title":"Durable lymphocyte subset elimination upon a single dose of AAV-delivered depletion antibody dissects immune control of chronic viral infection","authors":"Anna Lena Kastner, Anna-Friederike Marx, Mirela Dimitrova, Tiago Abreu-Mota, Yusuf I. Ertuna, Weldy V. Bonilla, Karsten Stauffer, Marco Künzli, Ingrid Wagner, Mario Kreutzfeldt, Doron Merkler, Daniel D. Pinschewer","doi":"10.1016/j.immuni.2024.11.021","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.11.021","url":null,"abstract":"To interrogate the role of specific immune cells in infection, cancer, and autoimmunity, immunologists commonly use monoclonal depletion antibodies (depletion-mAbs) or genetically engineered mouse models (GEMMs). To generate a tool that combines specific advantages and avoids select drawbacks of the two methods, we engineered adeno-associated viral vectors expressing depletion mAbs (depletion-AAVs). Single-dose depletion-AAV administration durably eliminated lymphocyte subsets in mice and avoided accessory deficiencies of GEMMs, such as marginal zone defects in B cell-deficient animals. Depletion-AAVs can be used in animals of different genetic backgrounds, and multiple depletion-AAVs can readily be combined. Exploiting depletion-AAV technology, we showed that B cells were required for unimpaired CD4<sup>+</sup> and CD8<sup>+</sup> T cell responses to chronic lymphocytic choriomeningitis virus (LCMV) infection. Upon B cell depletion, CD8<sup>+</sup> T cells failed to suppress viremia, and they only helped resolve chronic infection when antibodies dampened viral loads. Our study positions depletion-AAVs as a versatile tool for immunological research.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"14 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142874565","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 : 2024-12-23DOI: 10.1016/j.immuni.2024.11.020
Youliang Rao, Chao Qin, Ali Can Savas, Qizhi Liu, Shu Feng, Guoli Hou, Taolin Xie, Pinghui Feng
Metabolism is typically contextualized in conjunction with proliferation and growth. The roles of metabolic enzymes beyond metabolism—such as in innate immune responses—are underexplored. Using a focused short hairpin RNA (shRNA)-mediated screen, we identified CTP synthetase 1 (CTPS1), a rate-limiting enzyme of pyrimidine synthesis, as a negative regulator of interferon induction. Mechanistically, CTPS1 interacts with and deamidates interferon regulatory factor 3 (IRF3). Deamidation at N85 impairs IRF3 binding to promoters containing IRF3-responsive elements, thus muting interferon (IFN) induction. Employing CTPS1 conditional deletion and IRF3 deamidated or deamidation-resistant knockin mice, we demonstrated that CTPS1-driven IRF3 deamidation restricts IFN induction in response to viral infection in vivo. However, during immune activation, IRF3 deamidation by CTPS1 is inhibited by glycogen synthase kinase 3 beta (GSK3β) to promote IFN induction. This work demonstrates how CTPS1 tames innate immunity independent of its role in pyrimidine synthesis, thus expanding the functional repertoire of metabolic enzymes into immune regulation.
{"title":"Pyrimidine synthesis enzyme CTP synthetase 1 suppresses antiviral interferon induction by deamidating IRF3","authors":"Youliang Rao, Chao Qin, Ali Can Savas, Qizhi Liu, Shu Feng, Guoli Hou, Taolin Xie, Pinghui Feng","doi":"10.1016/j.immuni.2024.11.020","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.11.020","url":null,"abstract":"Metabolism is typically contextualized in conjunction with proliferation and growth. The roles of metabolic enzymes beyond metabolism—such as in innate immune responses—are underexplored. Using a focused short hairpin RNA (shRNA)-mediated screen, we identified CTP synthetase 1 (CTPS1), a rate-limiting enzyme of pyrimidine synthesis, as a negative regulator of interferon induction. Mechanistically, CTPS1 interacts with and deamidates interferon regulatory factor 3 (IRF3). Deamidation at N85 impairs IRF3 binding to promoters containing IRF3-responsive elements, thus muting interferon (IFN) induction. Employing CTPS1 conditional deletion and IRF3 deamidated or deamidation-resistant knockin mice, we demonstrated that CTPS1-driven IRF3 deamidation restricts IFN induction in response to viral infection in vivo. However, during immune activation, IRF3 deamidation by CTPS1 is inhibited by glycogen synthase kinase 3 beta (GSK3β) to promote IFN induction. This work demonstrates how CTPS1 tames innate immunity independent of its role in pyrimidine synthesis, thus expanding the functional repertoire of metabolic enzymes into immune regulation.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"32 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142874562","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 : 2024-12-20DOI: 10.1016/j.immuni.2024.11.007
Milcah C. Scott, Zoë Steier, Mark J. Pierson, J. Michael Stolley, Stephen D. O’Flanagan, Andrew G. Soerens, Sathi P. Wijeyesinghe, Lalit K. Beura, Gayathri Dileepan, Brandon J. Burbach, Marco Künzli, Clare F. Quarnstrom, Olivia C. Ghirardelli Smith, Eyob Weyu, Sara E. Hamilton, Vaiva Vezys, Alex K. Shalek, David Masopust
Tissue-resident memory CD8+ T (Trm) cells control infections and cancer and are defined by their lack of recirculation. Because migration is difficult to assess, residence is usually inferred by putative residence-defining phenotypic and gene signature proxies. We assessed the validity and universality of residence proxies by integrating mouse parabiosis, multi-organ sampling, intravascular staining, acute and chronic infection models, dirty mice, and single-cell multi-omics. We report that memory T cells integrate a constellation of inputs—location, stimulation history, antigen persistence, and environment—resulting in myriad differentiation states. Thus, current Trm-defining methodologies have implicit limitations, and a universal residence-specific signature may not exist. However, we define genes and phenotypes that more robustly correlate with tissue residence across the broad range of conditions that we tested. This study reveals broad adaptability of T cells to diverse stimulatory and environmental inputs and provides practical recommendations for evaluating Trm cells.
组织驻留记忆CD8+ T （Trm）细胞控制感染和癌症，并被定义为缺乏再循环。由于迁移难以评估，居住通常是通过假定的居住定义表型和基因标记代理来推断的。我们通过整合小鼠异种共生、多器官取样、血管内染色、急性和慢性感染模型、脏小鼠和单细胞多组学来评估驻留代理的有效性和普遍性。我们报道记忆T细胞整合了一系列输入-位置，刺激历史，抗原持久性和环境-导致无数的分化状态。因此，当前的trm定义方法具有隐含的局限性，并且可能不存在通用的特定于住所的签名。然而，我们定义了基因和表型，这些基因和表型与我们测试的广泛条件下的组织驻留更紧密相关。该研究揭示了T细胞对各种刺激和环境输入的广泛适应性，并为评估Trm细胞提供了实用建议。
{"title":"Deep profiling deconstructs features associated with memory CD8+ T cell tissue residence","authors":"Milcah C. Scott, Zoë Steier, Mark J. Pierson, J. Michael Stolley, Stephen D. O’Flanagan, Andrew G. Soerens, Sathi P. Wijeyesinghe, Lalit K. Beura, Gayathri Dileepan, Brandon J. Burbach, Marco Künzli, Clare F. Quarnstrom, Olivia C. Ghirardelli Smith, Eyob Weyu, Sara E. Hamilton, Vaiva Vezys, Alex K. Shalek, David Masopust","doi":"10.1016/j.immuni.2024.11.007","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.11.007","url":null,"abstract":"Tissue-resident memory CD8<sup>+</sup> T (Trm) cells control infections and cancer and are defined by their lack of recirculation. Because migration is difficult to assess, residence is usually inferred by putative residence-defining phenotypic and gene signature proxies. We assessed the validity and universality of residence proxies by integrating mouse parabiosis, multi-organ sampling, intravascular staining, acute and chronic infection models, dirty mice, and single-cell multi-omics. We report that memory T cells integrate a constellation of inputs—location, stimulation history, antigen persistence, and environment—resulting in myriad differentiation states. Thus, current Trm-defining methodologies have implicit limitations, and a universal residence-specific signature may not exist. However, we define genes and phenotypes that more robustly correlate with tissue residence across the broad range of conditions that we tested. This study reveals broad adaptability of T cells to diverse stimulatory and environmental inputs and provides practical recommendations for evaluating Trm cells.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"22 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142857805","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 : 2024-12-18DOI: 10.1016/j.immuni.2024.11.019
Andrew Chancellor, Daniel Constantin, , Qinmei Yang, Vladimir Nosi, José Pedro Loureiro, Rodrigo Colombo, Roman P. Jakob, Daniel Joss, Michael Pfeffer, Giulia De Simone, Aurelia Morabito, Verena Schaefer, Alessandro Vacchini, Laura Brunelli, Daniela Montagna, Markus Heim, Alfred Zippelius, Enrico Davoli, Daniel Häussinger, Gennaro De Libero
The major histocompatibility complex (MHC) class I-related molecule MHC-class-I-related protein 1 (MR1) presents metabolites to distinct MR1-restricted T cell subsets, including mucosal-associated invariant T (MAIT) and MR1T cells. However, self-reactive MR1T cells and the nature of recognized antigens remain underexplored. Here, we report a cell endogenous carbonyl adduct of adenine (8-(9H-purin-6-yl)-2-oxa-8-azabicyclo[3.3.1]nona-3,6-diene-4,6-dicarbaldehyde [M3Ade]) sequestered in the A′ pocket of MR1. M3Ade induced in vitro MR1-mediated stimulation of MR1T cell clones that bound MR1-M3Ade tetramers. MR1-M3Ade tetramers identified heterogeneous MR1-reactive T cells ex vivo in healthy donors, individuals with acute myeloid leukemia, and tumor-infiltrating lymphocytes from non-small cell lung adenocarcinoma and hepatocarcinoma. These cells displayed phenotypic, transcriptional, and functional diversity at distinct differentiation stages, indicating their adaptive nature. They were also polyclonal, with some preferential T cell receptor (TCRαβ) pair usage. Thus, M3Ade is an MR1-presented self-metabolite that enables stimulation and tracking of human-MR1T cells from blood and tissue, aiding our understanding of their roles in health and disease.
{"title":"The carbonyl nucleobase adduct M3Ade is a potent antigen for adaptive polyclonal MR1-restricted T cells","authors":"Andrew Chancellor, Daniel Constantin, , Qinmei Yang, Vladimir Nosi, José Pedro Loureiro, Rodrigo Colombo, Roman P. Jakob, Daniel Joss, Michael Pfeffer, Giulia De Simone, Aurelia Morabito, Verena Schaefer, Alessandro Vacchini, Laura Brunelli, Daniela Montagna, Markus Heim, Alfred Zippelius, Enrico Davoli, Daniel Häussinger, Gennaro De Libero","doi":"10.1016/j.immuni.2024.11.019","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.11.019","url":null,"abstract":"The major histocompatibility complex (MHC) class I-related molecule MHC-class-I-related protein 1 (MR1) presents metabolites to distinct MR1-restricted T cell subsets, including mucosal-associated invariant T (MAIT) and MR1T cells. However, self-reactive MR1T cells and the nature of recognized antigens remain underexplored. Here, we report a cell endogenous carbonyl adduct of adenine (8-(9H-purin-6-yl)-2-oxa-8-azabicyclo[3.3.1]nona-3,6-diene-4,6-dicarbaldehyde [M<sub>3</sub>Ade]) sequestered in the A′ pocket of MR1. M<sub>3</sub>Ade induced <em>in vitro</em> MR1-mediated stimulation of MR1T cell clones that bound MR1-M<sub>3</sub>Ade tetramers. MR1-M<sub>3</sub>Ade tetramers identified heterogeneous MR1-reactive T cells <em>ex vivo</em> in healthy donors, individuals with acute myeloid leukemia, and tumor-infiltrating lymphocytes from non-small cell lung adenocarcinoma and hepatocarcinoma. These cells displayed phenotypic, transcriptional, and functional diversity at distinct differentiation stages, indicating their adaptive nature. They were also polyclonal, with some preferential T cell receptor (TCRαβ) pair usage. Thus, M<sub>3</sub>Ade is an MR1-presented self-metabolite that enables stimulation and tracking of human-MR1T cells from blood and tissue, aiding our understanding of their roles in health and disease.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"78 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142841517","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}
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