Pub Date : 2025-10-17DOI: 10.1126/sciimmunol.ado3825
Artem Kalinichenko, Jakob Huemer, Theresa Humer, Matthias Haimel, Michael Svaton, Nicolas Socquet-Juglard, Giovanna Perinetti Casoni, Celine Prakash, Maximilian von der Linde, Julia Pazmandi, Cheryl van de Wetering, Javier Nunez-Fontarnau, Anton Kamnev, Sarah Giuliani, Martin G. Jaeger, Elisa Hahn, Sarah Dobner, Andrea Rukavina, Elise Sylvander, Jacqueline Seigner, Christina Rashkova, Birgit Hoeger, Michael W. Traxlmayr, Manfred Lehner, Yenan T. Bryceson, Janna Saarela, Thomas Hannich, Irinka Castanon, Georg Winter, Loïc Dupré, Kaan Boztug
Regulated exocytosis controls key cellular functions ranging from neurotransmitter release to the secretion of immune mediators, and its disruption is associated with numerous pathologies. The cytotoxic activity of lymphocytes is particularly dependent on regulated and polarized lytic granule delivery toward infected or malignant cells. Although genetic and mechanistic studies have identified factors regulating exocytosis in cytotoxic lymphocytes, a systematic mapping of the relevant factors and their relationships is lacking. Through a genome-scale CRISPR knockout screen in a human natural killer cell line, we characterized a complex genetic network regulating cytotoxic granule exocytosis, with lipid metabolism and protein lipidation among the most prominent pathways. By combining global protein palmitoylation and lipidomic studies, we found that ZDHHC17 drives palmitoylation of the core SNARE complex protein SNAP23 to target cytotoxic granules to GM1-rich lipid rafts whose assembly is controlled by serine palmitoyltransferase. In summary, our study identifies previously unrecognized factors essential for cytotoxic function in human lymphocytes and uncovers how lipid metabolism and protein palmitoylation are involved in the process of regulated exocytosis.
{"title":"Protein palmitoylation and sphingolipid metabolism control regulated exocytosis in cytotoxic lymphocytes","authors":"Artem Kalinichenko, Jakob Huemer, Theresa Humer, Matthias Haimel, Michael Svaton, Nicolas Socquet-Juglard, Giovanna Perinetti Casoni, Celine Prakash, Maximilian von der Linde, Julia Pazmandi, Cheryl van de Wetering, Javier Nunez-Fontarnau, Anton Kamnev, Sarah Giuliani, Martin G. Jaeger, Elisa Hahn, Sarah Dobner, Andrea Rukavina, Elise Sylvander, Jacqueline Seigner, Christina Rashkova, Birgit Hoeger, Michael W. Traxlmayr, Manfred Lehner, Yenan T. Bryceson, Janna Saarela, Thomas Hannich, Irinka Castanon, Georg Winter, Loïc Dupré, Kaan Boztug","doi":"10.1126/sciimmunol.ado3825","DOIUrl":"10.1126/sciimmunol.ado3825","url":null,"abstract":"<div >Regulated exocytosis controls key cellular functions ranging from neurotransmitter release to the secretion of immune mediators, and its disruption is associated with numerous pathologies. The cytotoxic activity of lymphocytes is particularly dependent on regulated and polarized lytic granule delivery toward infected or malignant cells. Although genetic and mechanistic studies have identified factors regulating exocytosis in cytotoxic lymphocytes, a systematic mapping of the relevant factors and their relationships is lacking. Through a genome-scale CRISPR knockout screen in a human natural killer cell line, we characterized a complex genetic network regulating cytotoxic granule exocytosis, with lipid metabolism and protein lipidation among the most prominent pathways. By combining global protein palmitoylation and lipidomic studies, we found that ZDHHC17 drives palmitoylation of the core SNARE complex protein SNAP23 to target cytotoxic granules to GM1-rich lipid rafts whose assembly is controlled by serine palmitoyltransferase. In summary, our study identifies previously unrecognized factors essential for cytotoxic function in human lymphocytes and uncovers how lipid metabolism and protein palmitoylation are involved in the process of regulated exocytosis.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 112","pages":""},"PeriodicalIF":16.3,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145310782","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 : 2025-10-10DOI: 10.1126/sciimmunol.aec5738
{"title":"Erratum for the Research Article “METTL1-mediated m7G methylation of Sarm1 mRNA promotes macrophage inflammatory responses and multiple organ injury” by C. Hou et al.","authors":"","doi":"10.1126/sciimmunol.aec5738","DOIUrl":"10.1126/sciimmunol.aec5738","url":null,"abstract":"","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 112","pages":""},"PeriodicalIF":16.3,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145256882","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 : 2025-10-10DOI: 10.1126/sciimmunol.adu4107
Sameer Kumar Malladi, Deepika Jaiswal, Baoling Ying, Wafaa B. Alsoussi, Tamarand L. Darling, Bernadeta Dadonaite, Alesandro Civljak, Stephen C. Horvath, Julian Q. Zhou, Wooseob Kim, Jackson S. Turner, Aaron J. Schmitz, Fangjie Han, Suzanne M. Scheaffer, Christopher W. Farnsworth, Raffael Nachbagauer, Biliana Nestorova, Spyros Chalkias, Michael K. Klebert, Darin K. Edwards, Robert Paris, Benjamin S. Strnad, William D. Middleton, Jane A. O’Halloran, Rachel M. Presti, Jesse D. Bloom, Adrianus C. M. Boon, Michael S. Diamond, Goran Bajic, Ali H. Ellebedy
Germinal centers (GCs) are key sites for antibody diversification and affinity maturation. SARS-CoV-2 messenger RNA (mRNA) vaccines elicit robust GC B cell responses in humans, but how these responses influence the breadth of immunity against viral variants remains unclear. We analyzed GC B cell responses in nine healthy adults after mRNA booster immunization. We show that 77.8% of the B cell clones in the GC expressed representative monoclonal antibodies (mAbs) recognizing the spike protein, with 37.8% of these targeting the receptor binding domain (RBD). One RBD-targeting mAb, mAb-52, neutralized all tested SARS-CoV-2 strains, including the recent XEC variant. mAb-52 used the IGHV3-66 public clonotype, protected hamsters challenged against the EG.5.1 variant, and targeted the class I/II RBD epitope, closely mimicking the binding footprint of ACE2. Its broad reactivity was driven by extensive somatic hypermutation, underscoring the critical role of GC reactions in shaping cross-variant B cell immunity after SARS-CoV-2 booster vaccination.
{"title":"Germinal center–mediated broadening of B cell responses to SARS-CoV-2 booster immunization","authors":"Sameer Kumar Malladi, Deepika Jaiswal, Baoling Ying, Wafaa B. Alsoussi, Tamarand L. Darling, Bernadeta Dadonaite, Alesandro Civljak, Stephen C. Horvath, Julian Q. Zhou, Wooseob Kim, Jackson S. Turner, Aaron J. Schmitz, Fangjie Han, Suzanne M. Scheaffer, Christopher W. Farnsworth, Raffael Nachbagauer, Biliana Nestorova, Spyros Chalkias, Michael K. Klebert, Darin K. Edwards, Robert Paris, Benjamin S. Strnad, William D. Middleton, Jane A. O’Halloran, Rachel M. Presti, Jesse D. Bloom, Adrianus C. M. Boon, Michael S. Diamond, Goran Bajic, Ali H. Ellebedy","doi":"10.1126/sciimmunol.adu4107","DOIUrl":"10.1126/sciimmunol.adu4107","url":null,"abstract":"<div >Germinal centers (GCs) are key sites for antibody diversification and affinity maturation. SARS-CoV-2 messenger RNA (mRNA) vaccines elicit robust GC B cell responses in humans, but how these responses influence the breadth of immunity against viral variants remains unclear. We analyzed GC B cell responses in nine healthy adults after mRNA booster immunization. We show that 77.8% of the B cell clones in the GC expressed representative monoclonal antibodies (mAbs) recognizing the spike protein, with 37.8% of these targeting the receptor binding domain (RBD). One RBD-targeting mAb, mAb-52, neutralized all tested SARS-CoV-2 strains, including the recent XEC variant. mAb-52 used the <i>IGHV3-66</i> public clonotype, protected hamsters challenged against the EG.5.1 variant, and targeted the class I/II RBD epitope, closely mimicking the binding footprint of ACE2. Its broad reactivity was driven by extensive somatic hypermutation, underscoring the critical role of GC reactions in shaping cross-variant B cell immunity after SARS-CoV-2 booster vaccination.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 112","pages":""},"PeriodicalIF":16.3,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adu4107","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145255626","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 : 2025-10-10DOI: 10.1126/sciimmunol.adv5085
Zhenghai Tang, Ming-Chao Zhong, Jin Qian, Jiayu Dou, Lok San Wong, Jiaxin Li, Cristian Camilo Galindo, Dominique Davidson, André Veillette
Signal regulatory protein α (SIRPα) is a macrophage inhibitory receptor that limits phagocytosis and antitumor activity by interacting in trans with CD47 on tumor cells. Here, we found that a component of SIRPα’s inhibitory function occurred independently of CD47. Inhibition occurred because of interactions between SIRPα and CD18 (β2 integrin) in cis on the surface of macrophages, involving SIRPα amino acids distinct from those implicated in the SIRPα-CD47 interaction. This cis interaction prevented activation of CD18, which is necessary for phagocytosis. The combined blockade of SIRPα-CD18 and SIRPα-CD47 was essential for maximizing phagocytosis and suppression of tumor growth in vivo. Thus, inhibitory immune checkpoints such as SIRPα suppress cell activation through a mechanism targeting CD18 in cis, which occurs in addition to engagement by their inhibitory checkpoint ligands in trans. This dual mode of action should be considered when developing inhibitory checkpoint blockades for immunotherapy.
{"title":"Anticancer immune responses are hindered by cis interaction of inhibitory checkpoint SIRPα","authors":"Zhenghai Tang, Ming-Chao Zhong, Jin Qian, Jiayu Dou, Lok San Wong, Jiaxin Li, Cristian Camilo Galindo, Dominique Davidson, André Veillette","doi":"10.1126/sciimmunol.adv5085","DOIUrl":"10.1126/sciimmunol.adv5085","url":null,"abstract":"<div >Signal regulatory protein α (SIRPα) is a macrophage inhibitory receptor that limits phagocytosis and antitumor activity by interacting in trans with CD47 on tumor cells. Here, we found that a component of SIRPα’s inhibitory function occurred independently of CD47. Inhibition occurred because of interactions between SIRPα and CD18 (β<sub>2</sub> integrin) in cis on the surface of macrophages, involving SIRPα amino acids distinct from those implicated in the SIRPα-CD47 interaction. This cis interaction prevented activation of CD18, which is necessary for phagocytosis. The combined blockade of SIRPα-CD18 and SIRPα-CD47 was essential for maximizing phagocytosis and suppression of tumor growth in vivo. Thus, inhibitory immune checkpoints such as SIRPα suppress cell activation through a mechanism targeting CD18 in cis, which occurs in addition to engagement by their inhibitory checkpoint ligands in trans. This dual mode of action should be considered when developing inhibitory checkpoint blockades for immunotherapy.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 112","pages":""},"PeriodicalIF":16.3,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145255627","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 : 2025-10-03DOI: 10.1126/sciimmunol.aec5741
Elise G. Liu, Adam Williams
Food antigen–specific peripheral regulatory T cell induction in the gut is driven by RORγt+ dendritic cells.
肠道中食物抗原特异性外周调节性T细胞的诱导是由RORγt+树突状细胞驱动的。
{"title":"The power of the few: RORγt+ dendritic cells promote food-specific peripheral regulatory T cells","authors":"Elise G. Liu, Adam Williams","doi":"10.1126/sciimmunol.aec5741","DOIUrl":"10.1126/sciimmunol.aec5741","url":null,"abstract":"<div >Food antigen–specific peripheral regulatory T cell induction in the gut is driven by RORγt<sup>+</sup> dendritic cells.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 112","pages":""},"PeriodicalIF":16.3,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145211067","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 : 2025-10-03DOI: 10.1126/sciimmunol.aec5745
Francesca Beretta, Valentina Damato
A desmoglein-3 antigen-Fc fusion construct shows promise as a therapeutic in a model of pemphigus vulgaris.
粘粒蛋白-3抗原- fc融合结构在寻常型天疱疮模型中显示出治疗的希望。
{"title":"Taking aim at autoimmunity—Antigen-Fc constructs for mucosal pemphigus hit the mark","authors":"Francesca Beretta, Valentina Damato","doi":"10.1126/sciimmunol.aec5745","DOIUrl":"10.1126/sciimmunol.aec5745","url":null,"abstract":"<div >A desmoglein-3 antigen-Fc fusion construct shows promise as a therapeutic in a model of pemphigus vulgaris.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 112","pages":""},"PeriodicalIF":16.3,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145211069","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 : 2025-10-03DOI: 10.1126/sciimmunol.ads0449
Lukas Bunse, Theresa Bunse, Michael Kilian, Francisco J. Quintana, Michael Platten
Brain tumors represent a unique challenge for cancer immunotherapies because of their location in an immune privileged site. However, the brain tumor immune microenvironment is dictated more by tumor type than the location within the brain per se. This feature is reflected by the higher immunogenicity and response to immunotherapies of metastatic brain tumors compared with primary brain tumors. Immunotherapies for brain tumors aim at inducing and boosting tumor T cell responses using vaccines, immune checkpoint inhibitors, or adoptive T cell therapies. A fundamental challenge in the field is how such brain tumor–targeting T cells gain access to brain tumors and maintain their function despite a hostile immunosuppressive microenvironment. Here, we review current knowledge of the cellular and molecular determinants of the antigenicity of brain tumors and the immunosuppressive brain tumor microenvironment. Expanding and exploiting this knowledge will provide the key for effective combinatorial therapies.
{"title":"The immunology of brain tumors","authors":"Lukas Bunse, Theresa Bunse, Michael Kilian, Francisco J. Quintana, Michael Platten","doi":"10.1126/sciimmunol.ads0449","DOIUrl":"10.1126/sciimmunol.ads0449","url":null,"abstract":"<div >Brain tumors represent a unique challenge for cancer immunotherapies because of their location in an immune privileged site. However, the brain tumor immune microenvironment is dictated more by tumor type than the location within the brain per se. This feature is reflected by the higher immunogenicity and response to immunotherapies of metastatic brain tumors compared with primary brain tumors. Immunotherapies for brain tumors aim at inducing and boosting tumor T cell responses using vaccines, immune checkpoint inhibitors, or adoptive T cell therapies. A fundamental challenge in the field is how such brain tumor–targeting T cells gain access to brain tumors and maintain their function despite a hostile immunosuppressive microenvironment. Here, we review current knowledge of the cellular and molecular determinants of the antigenicity of brain tumors and the immunosuppressive brain tumor microenvironment. Expanding and exploiting this knowledge will provide the key for effective combinatorial therapies.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 112","pages":""},"PeriodicalIF":16.3,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.ads0449","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145210010","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 : 2025-10-03DOI: 10.1126/sciimmunol.adu6730
Katharina Kocher, Felix Drost, Abel Mekonnen Tesfaye, Carolin Moosmann, Christine Schülein, Myriam Grotz, Elvira D’Ippolito, Frederik Graw, Bernd Spriewald, Dirk H. Busch, Christian Bogdan, Matthias Tenbusch, Benjamin Schubert, Kilian Schober
Clonal expansion is a hallmark of adaptive immunity and has been challenging to investigate in humans in a standardized manner compared with animal models. We studied a cohort of 29 healthy individuals who received three mRNA vaccinations against SARS-CoV-2 before a breakthrough infection. We characterized the magnitude, phenotype, and clonal composition of CD8 T cell responses against 16 epitope specificities by ELISpot; flow cytometry; and single-cell RNA, protein, and T cell receptor (TCR) sequencing. One hundred six TCRs from five epitope-specific repertoires were reexpressed and tested for peptide sensitivity. Whereas vaccination-recruited T cell repertoires were enriched for high-avidity TCRs, differential clonal expansion was not linked to fine avidity differences. Instead, maintenance of polyclonality ensured robustness in counteracting viral mutational escape through altered epitopes. Deciphering the functionality of human antigen-specific T cell repertoires instructs our understanding of human T cell biology and may guide the development of vaccines and other immunotherapies.
{"title":"Vaccination-induced T cell responses maintain polyclonality with high antigen receptor avidity","authors":"Katharina Kocher, Felix Drost, Abel Mekonnen Tesfaye, Carolin Moosmann, Christine Schülein, Myriam Grotz, Elvira D’Ippolito, Frederik Graw, Bernd Spriewald, Dirk H. Busch, Christian Bogdan, Matthias Tenbusch, Benjamin Schubert, Kilian Schober","doi":"10.1126/sciimmunol.adu6730","DOIUrl":"10.1126/sciimmunol.adu6730","url":null,"abstract":"<div >Clonal expansion is a hallmark of adaptive immunity and has been challenging to investigate in humans in a standardized manner compared with animal models. We studied a cohort of 29 healthy individuals who received three mRNA vaccinations against SARS-CoV-2 before a breakthrough infection. We characterized the magnitude, phenotype, and clonal composition of CD8 T cell responses against 16 epitope specificities by ELISpot; flow cytometry; and single-cell RNA, protein, and T cell receptor (TCR) sequencing. One hundred six TCRs from five epitope-specific repertoires were reexpressed and tested for peptide sensitivity. Whereas vaccination-recruited T cell repertoires were enriched for high-avidity TCRs, differential clonal expansion was not linked to fine avidity differences. Instead, maintenance of polyclonality ensured robustness in counteracting viral mutational escape through altered epitopes. Deciphering the functionality of human antigen-specific T cell repertoires instructs our understanding of human T cell biology and may guide the development of vaccines and other immunotherapies.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 112","pages":""},"PeriodicalIF":16.3,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145209972","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 : 2025-09-26DOI: 10.1126/sciimmunol.adx1582
Jung-Ho Chun, Birkley S. Lim, Suyasha Roy, Michael J. Walsh, Gita C. Abhiraman, Kevin Zhangxu, Tavus Atajanova, Or-Yam Revach, Elisa C. Clark, Peng Li, Claire A. Palin, Asheema Khanna, Samantha Tower, Rakeeb Kureshi, Megan T. Hoffman, Tatyana Sharova, Aleigha Lawless, Sonia Cohen, Genevieve M. Boland, Tina Nguyen, Frank Peprah, Julissa G. Tello, Samantha Y. Liu, Chan Johng Kim, Hojeong Shin, Alfredo Quijano-Rubio, Kevin M. Jude, Stacey Gerben, Analisa Murray, Piper Heine, Michelle DeWitt, Umut Y. Ulge, Lauren Carter, Neil P. King, Daniel-Adriano Silva, Hao Yuan Kueh, Vandana Kalia, Surojit Sarkar, Russell W. Jenkins, K. Christopher Garcia, Warren J. Leonard, Michael Dougan, Stephanie K. Dougan, David Baker
Long-standing goals of cancer immunotherapy are to activate cytotoxic antitumor T cells across a range of affinities for tumor antigens while suppressing regulatory T cells. Computational protein design has enabled the precise tailoring of proteins to meet specific needs. Here, we report a de novo designed IL-21 mimic, 21h10, with high stability and signaling potency in humans and mice. In murine and ex vivo human organotypic tumor models, 21h10 showed robust antitumor activity, with more prolonged signaling and stronger antitumor activity than native IL-21. 21h10 induced pancreatitis that could be mitigated by TNF blockade without compromising antitumor efficacy. Although antidrug antibodies to 21h10 formed, they were not neutralizing. 21h10 induced highly cytotoxic T cells with a range of affinities, robustly expanding intratumoral low-affinity cytotoxic T cells and driving high expression of IFN-γ and granzyme B compared with native IL-21, while increasing the frequency of IFN-γ+ T helper 1 cells and reducing regulatory T cells. The full human-mouse cross-reactivity, high stability and potency, and low-affinity antitumor responses support the translational potential of 21h10.
{"title":"Design of a potent interleukin-21 mimic for cancer immunotherapy","authors":"Jung-Ho Chun, Birkley S. Lim, Suyasha Roy, Michael J. Walsh, Gita C. Abhiraman, Kevin Zhangxu, Tavus Atajanova, Or-Yam Revach, Elisa C. Clark, Peng Li, Claire A. Palin, Asheema Khanna, Samantha Tower, Rakeeb Kureshi, Megan T. Hoffman, Tatyana Sharova, Aleigha Lawless, Sonia Cohen, Genevieve M. Boland, Tina Nguyen, Frank Peprah, Julissa G. Tello, Samantha Y. Liu, Chan Johng Kim, Hojeong Shin, Alfredo Quijano-Rubio, Kevin M. Jude, Stacey Gerben, Analisa Murray, Piper Heine, Michelle DeWitt, Umut Y. Ulge, Lauren Carter, Neil P. King, Daniel-Adriano Silva, Hao Yuan Kueh, Vandana Kalia, Surojit Sarkar, Russell W. Jenkins, K. Christopher Garcia, Warren J. Leonard, Michael Dougan, Stephanie K. Dougan, David Baker","doi":"10.1126/sciimmunol.adx1582","DOIUrl":"10.1126/sciimmunol.adx1582","url":null,"abstract":"<div >Long-standing goals of cancer immunotherapy are to activate cytotoxic antitumor T cells across a range of affinities for tumor antigens while suppressing regulatory T cells. Computational protein design has enabled the precise tailoring of proteins to meet specific needs. Here, we report a de novo designed IL-21 mimic, 21h10, with high stability and signaling potency in humans and mice. In murine and ex vivo human organotypic tumor models, 21h10 showed robust antitumor activity, with more prolonged signaling and stronger antitumor activity than native IL-21. 21h10 induced pancreatitis that could be mitigated by TNF blockade without compromising antitumor efficacy. Although antidrug antibodies to 21h10 formed, they were not neutralizing. 21h10 induced highly cytotoxic T cells with a range of affinities, robustly expanding intratumoral low-affinity cytotoxic T cells and driving high expression of IFN-γ and granzyme B compared with native IL-21, while increasing the frequency of IFN-γ<sup>+</sup> T helper 1 cells and reducing regulatory T cells. The full human-mouse cross-reactivity, high stability and potency, and low-affinity antitumor responses support the translational potential of 21h10.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 111","pages":""},"PeriodicalIF":16.3,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adx1582","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145141193","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 : 2025-09-26DOI: 10.1126/sciimmunol.adp7092
Divija Deshpande, Laura Velleman, Janna Schmitz, Patrycja M. Forster, Christian Schinke, Sotiria Boulekou, Henning Peter Düsedau, Susanne M. Krug, Till Mertens, Xuemei Gao, Caio Figueiredo, Katja J. Jarick, Thomas Plum, Nele Sterczyk, Pierre S. Leclère, Sofia Helfrich, Anke Tappe-Theodor, Katja Kotsch, Johannes Steffen, David Voehringer, Claudia U. Duerr, Anja E. Hauser, David Artis, Claudia Pitzer, Ildiko R. Dunay, Christoph S. N. Klose
The peripheral nervous system (PNS) is involved in nociception and gait. The contribution of PNS-resident immune cells to these functions is not fully understood. We identified group 2 innate lymphoid cells (ILC2s) as a distinct immune cell population resident in the PNS, with a unique gene profile facilitating neuron-ILC2 cross-talk. ILC2-deficient mice display PNS dysfunction (hypersensitivity and gait anomalies). These functional deficits are attributed to structural abnormalities in the sciatic nerves of ILC2-deficient mice. ILC2s communicate with dorsal root ganglion neurons via the interleukin-13 (IL-13) signaling pathway to maintain nerve structure and pain thresholds. Loss of the shared IL-4/IL-13 receptor (IL-4R/IL-13R) in neurons results in a phenotype similar to ILC2-deficient mice. Intrathecally administered IL-13 rescues hypersensitivity and gait defects in ILC2-deficient mice, which suggests that this signaling pathway may be therapeutically important. This work therefore identifies a function for ILC2s in regulating the nerve structural integrity and nociceptive functions of the PNS.
{"title":"Group 2 innate lymphoid cells regulate nociceptive and gait functions of the peripheral nervous system","authors":"Divija Deshpande, Laura Velleman, Janna Schmitz, Patrycja M. Forster, Christian Schinke, Sotiria Boulekou, Henning Peter Düsedau, Susanne M. Krug, Till Mertens, Xuemei Gao, Caio Figueiredo, Katja J. Jarick, Thomas Plum, Nele Sterczyk, Pierre S. Leclère, Sofia Helfrich, Anke Tappe-Theodor, Katja Kotsch, Johannes Steffen, David Voehringer, Claudia U. Duerr, Anja E. Hauser, David Artis, Claudia Pitzer, Ildiko R. Dunay, Christoph S. N. Klose","doi":"10.1126/sciimmunol.adp7092","DOIUrl":"10.1126/sciimmunol.adp7092","url":null,"abstract":"<div >The peripheral nervous system (PNS) is involved in nociception and gait. The contribution of PNS-resident immune cells to these functions is not fully understood. We identified group 2 innate lymphoid cells (ILC2s) as a distinct immune cell population resident in the PNS, with a unique gene profile facilitating neuron-ILC2 cross-talk. ILC2-deficient mice display PNS dysfunction (hypersensitivity and gait anomalies). These functional deficits are attributed to structural abnormalities in the sciatic nerves of ILC2-deficient mice. ILC2s communicate with dorsal root ganglion neurons via the interleukin-13 (IL-13) signaling pathway to maintain nerve structure and pain thresholds. Loss of the shared IL-4/IL-13 receptor (IL-4R/IL-13R) in neurons results in a phenotype similar to ILC2-deficient mice. Intrathecally administered IL-13 rescues hypersensitivity and gait defects in ILC2-deficient mice, which suggests that this signaling pathway may be therapeutically important. This work therefore identifies a function for ILC2s in regulating the nerve structural integrity and nociceptive functions of the PNS.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 111","pages":""},"PeriodicalIF":16.3,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adp7092","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145147022","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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