Pub Date : 2025-12-01DOI: 10.1016/j.immuni.2025.11.005
Britta Simons, Hieu Trong Nguyen, Atscharah Panyot, Fabian Tobias Hager, Johanna Kabbert, Asmae Laouina, Jonathan Schreiber, Lydia Kopplin, Tim Rollenske, Thomas Clavel, Oliver Pabst
Immunoglobulin A (IgA) is the most abundantly produced antibody isotype and mediates protection and homeostatic regulation at mucosal surfaces. Steady-state IgA production is supported by multiple pathways, including chronic germinal centers in gut inductive lymphoid tissues. However, we lack a detailed understanding of how IgA responses are temporally integrated across inductive and effector sites. Here, we dissect homeostatic IgA responses from the perspective of clonal repertoires in inductive compartments and the gut lamina propria as the main effector compartment. We show that unique clonal patterns dominate across gut inductive sites and that plasma cell (PC) clones in gut lamina propria entail progressive stages of differentiation. We demonstrate that ongoing diversification of recurrent clones continuously seeds the gut PC population. These observations suggest that clonal rather than cellular longevity shapes IgA responses and that dynamic modulation of recurrent clones may balance stability and flexibility of the gut PC repertoire.
{"title":"Clonal persistence dominates homeostatic intestinal IgA responses","authors":"Britta Simons, Hieu Trong Nguyen, Atscharah Panyot, Fabian Tobias Hager, Johanna Kabbert, Asmae Laouina, Jonathan Schreiber, Lydia Kopplin, Tim Rollenske, Thomas Clavel, Oliver Pabst","doi":"10.1016/j.immuni.2025.11.005","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.11.005","url":null,"abstract":"Immunoglobulin A (IgA) is the most abundantly produced antibody isotype and mediates protection and homeostatic regulation at mucosal surfaces. Steady-state IgA production is supported by multiple pathways, including chronic germinal centers in gut inductive lymphoid tissues. However, we lack a detailed understanding of how IgA responses are temporally integrated across inductive and effector sites. Here, we dissect homeostatic IgA responses from the perspective of clonal repertoires in inductive compartments and the gut lamina propria as the main effector compartment. We show that unique clonal patterns dominate across gut inductive sites and that plasma cell (PC) clones in gut lamina propria entail progressive stages of differentiation. We demonstrate that ongoing diversification of recurrent clones continuously seeds the gut PC population. These observations suggest that clonal rather than cellular longevity shapes IgA responses and that dynamic modulation of recurrent clones may balance stability and flexibility of the gut PC repertoire.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"22 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145651039","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 : 2025-11-28DOI: 10.1016/j.immuni.2025.11.007
Ananya Saha, Hasan Ahmed, Cora Hirst, Katia Koelle, Andreas Handel, Peter Teunis, Rustom Antia
Immunological memory is a defining feature of immunity, and a quantitative description of how it wanes would help better understand the processes underlying its maintenance and estimate the duration of protection after immunization. We analyzed the waning of antibodies to a panel of virus and vaccine antigens and found that a power-law model captured both the initial rapid decline and much slower subsequent waning. Importantly, accounting for the time post-immunization at which the waning was estimated reduced the difference between estimates for the rate of antibody waning to toxoid/protein vaccines and to live attenuated viruses. We found that protective levels of antibodies may be maintained for longer than previously estimated using exponential models fitted to data from the first decade following immunization. Our analyses indicate that the slow waning of antibodies over a time span of decades may be estimated from data from a shorter time frame of 2 to 3 years following immunization and stresses the importance of taking into account the time post-immunization at which antibody waning is estimated.
{"title":"Quantifying the waning of humoral immunity","authors":"Ananya Saha, Hasan Ahmed, Cora Hirst, Katia Koelle, Andreas Handel, Peter Teunis, Rustom Antia","doi":"10.1016/j.immuni.2025.11.007","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.11.007","url":null,"abstract":"Immunological memory is a defining feature of immunity, and a quantitative description of how it wanes would help better understand the processes underlying its maintenance and estimate the duration of protection after immunization. We analyzed the waning of antibodies to a panel of virus and vaccine antigens and found that a power-law model captured both the initial rapid decline and much slower subsequent waning. Importantly, accounting for the time post-immunization at which the waning was estimated reduced the difference between estimates for the rate of antibody waning to toxoid/protein vaccines and to live attenuated viruses. We found that protective levels of antibodies may be maintained for longer than previously estimated using exponential models fitted to data from the first decade following immunization. Our analyses indicate that the slow waning of antibodies over a time span of decades may be estimated from data from a shorter time frame of 2 to 3 years following immunization and stresses the importance of taking into account the time post-immunization at which antibody waning is estimated.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"9 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145611810","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 : 2025-11-26DOI: 10.1016/j.immuni.2025.10.025
Suhas Sureshchandra, James Henderson, Elizabeth Levendosky, Sankalan Bhattacharyya, Jenna M. Kastenschmidt, Andrew M. Sorn, Mahina Tabassum Mitul, Timothy B. Yates, Evien Cheng, Aviv Benchorin, Kyle Batucal, Allyssa Daugherty, Samuel J.H. Murphy, Chandrani Thakur, Douglas Trask, Gurpreet Ahuja, Qiu Zhong, Annie Moisan, Andreas Tiffeau-Mayer, Naresha Saligrama, Lisa E. Wagar
98% of T cells reside in tissues, yet nearly all human T cell analyses are performed on peripheral blood. We performed single-cell sequencing of 5.7 million T cells from autologous blood and tonsils of ten donors. We identified distinct patterns of clonal expansion associated with tonsil-restricted phenotypes. Clonal sharing between blood and tonsils was lower than previous estimates and increased with age. Identical T cell receptor (TCR) sequences exhibited limited concordance in their phenotypes across compartments. Furthermore, location dictated the frequencies, clonal dominance, and phenotypes of antigen-specific T cells. Using immune organoids, we showed that antigen exposure drives functionally distinct T cell clones from naive or tissue-resident memory pools. Finally, we demonstrate that chronic infections influence TCR repertoire diversity differently in blood and tonsil-resident T cells. These data highlight the necessity of accounting for tissue-specific contexts to accurately measure the TCR repertoire and monitor T cell responses following perturbing therapies.
{"title":"Deep profiling of human T cells defines compartmentalized clones and phenotypic trajectories across blood and tonsils","authors":"Suhas Sureshchandra, James Henderson, Elizabeth Levendosky, Sankalan Bhattacharyya, Jenna M. Kastenschmidt, Andrew M. Sorn, Mahina Tabassum Mitul, Timothy B. Yates, Evien Cheng, Aviv Benchorin, Kyle Batucal, Allyssa Daugherty, Samuel J.H. Murphy, Chandrani Thakur, Douglas Trask, Gurpreet Ahuja, Qiu Zhong, Annie Moisan, Andreas Tiffeau-Mayer, Naresha Saligrama, Lisa E. Wagar","doi":"10.1016/j.immuni.2025.10.025","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.10.025","url":null,"abstract":"98% of T cells reside in tissues, yet nearly all human T cell analyses are performed on peripheral blood. We performed single-cell sequencing of 5.7 million T cells from autologous blood and tonsils of ten donors. We identified distinct patterns of clonal expansion associated with tonsil-restricted phenotypes. Clonal sharing between blood and tonsils was lower than previous estimates and increased with age. Identical T cell receptor (TCR) sequences exhibited limited concordance in their phenotypes across compartments. Furthermore, location dictated the frequencies, clonal dominance, and phenotypes of antigen-specific T cells. Using immune organoids, we showed that antigen exposure drives functionally distinct T cell clones from naive or tissue-resident memory pools. Finally, we demonstrate that chronic infections influence TCR repertoire diversity differently in blood and tonsil-resident T cells. These data highlight the necessity of accounting for tissue-specific contexts to accurately measure the TCR repertoire and monitor T cell responses following perturbing therapies.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"5 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145600227","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 : 2025-11-26DOI: 10.1016/j.immuni.2025.11.003
Cameron L.R. Mattingly, Ariana R. Jimenez, M. Elliott Williams, Kirsten N. Kost, Laurel A. Lawrence, Thien Duy Chen, Sarah E. Michalets, Jenna L. Lobby, Yixel Soto-Vázquez, Kathryn M. Moore, Sakeenah L. Hicks, Shamika Danzy, Jennifer L. Elliott, Christopher D. Scharer, Alison Swaims-Kohlmeier, Anice C. Lowen, Aneesh Mehta, Jacob E. Kohlmeier
Lung resident CD8+ T cells are situated at the site of initial viral entry and replication. Here, we examined the phenotypic profiles and effector functions of human lung CD8+ T cells specific for four prevalent human viruses—influenza, respiratory syncytial virus (RSV), cytomegalovirus (CMV), and Epstein-Barr virus (EBV). Virus-specific lung CD8+ T cells exhibited distinct tissue-resident memory (Trm) phenotypes based on viral tropism yet shared core transcriptional and effector programs. Cognate antigen stimulation of lung Trm cells triggered interferon-γ (IFNγ)-mediated activation programs in lung innate immune and airway epithelial cells. Basal epithelial cells were most responsive to IFNγ, with differential expression of IFN-stimulated gene pathways in basal and secretory epithelial cell subsets following CD8+ Trm cell activation. In air-liquid interface cultures modeling influenza infection of the lung, rapid IFNγ signaling was necessary and sufficient to activate antiviral pathways in stratified epithelium and protect against infection. Thus, lung Trm cells coordinate early mucosal defense through rapid IFNγ-driven epithelial programming to restrict respiratory virus propagation in humans.
{"title":"Human lung CD8+ tissue-resident memory T cell-derived interferon-γ orchestrates subset-specific antiviral programming in airway epithelial cells","authors":"Cameron L.R. Mattingly, Ariana R. Jimenez, M. Elliott Williams, Kirsten N. Kost, Laurel A. Lawrence, Thien Duy Chen, Sarah E. Michalets, Jenna L. Lobby, Yixel Soto-Vázquez, Kathryn M. Moore, Sakeenah L. Hicks, Shamika Danzy, Jennifer L. Elliott, Christopher D. Scharer, Alison Swaims-Kohlmeier, Anice C. Lowen, Aneesh Mehta, Jacob E. Kohlmeier","doi":"10.1016/j.immuni.2025.11.003","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.11.003","url":null,"abstract":"Lung resident CD8<sup>+</sup> T cells are situated at the site of initial viral entry and replication. Here, we examined the phenotypic profiles and effector functions of human lung CD8<sup>+</sup> T cells specific for four prevalent human viruses—influenza, respiratory syncytial virus (RSV), cytomegalovirus (CMV), and Epstein-Barr virus (EBV). Virus-specific lung CD8<sup>+</sup> T cells exhibited distinct tissue-resident memory (Trm) phenotypes based on viral tropism yet shared core transcriptional and effector programs. Cognate antigen stimulation of lung Trm cells triggered interferon-γ (IFNγ)-mediated activation programs in lung innate immune and airway epithelial cells. Basal epithelial cells were most responsive to IFNγ, with differential expression of IFN-stimulated gene pathways in basal and secretory epithelial cell subsets following CD8<sup>+</sup> Trm cell activation. In air-liquid interface cultures modeling influenza infection of the lung, rapid IFNγ signaling was necessary and sufficient to activate antiviral pathways in stratified epithelium and protect against infection. Thus, lung Trm cells coordinate early mucosal defense through rapid IFNγ-driven epithelial programming to restrict respiratory virus propagation in humans.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"3 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145600178","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 : 2025-11-24DOI: 10.1016/j.immuni.2025.10.014
John T. Killian, R. Glenn King, Aaron C.K. Lucander, James L. Kizziah, Christopher F. Fucile, Ruben Diaz-Avalos, Shihong Qiu, Aaron Silva-Sanchez, Betty J. Mousseau, Kevin J. Macon, Amanda R. Callahan, Guang Yang, M. Emon Hossain, Jobaida Akther, Daryl B. Good, Susan Kelso, Julie A. Houp, Frida Rosenblum, Paige M. Porrett, Song C. Ong, Frances E. Lund
Donor-specific antibody responses against human leukocyte antigen (HLA) proteins mismatched between transplant donors and recipients cause allograft loss, yet the structural HLA epitopes targeted by alloreactive B cells and antibodies remain largely unresolved. We profiled the HLA-A∗01:01-specific B cell response in the transplanted kidney and blood of a recipient undergoing antibody-mediated rejection and identified immunodominant B cell and antibody responses that emerged early in the alloimmune response. These responses were focused on topographically exposed mismatched HLA residues located in the α helices along the peptide-binding groove of HLA-A∗01:01. We demonstrated that the anti-HLA-A∗01:01 B cell alloresponse converged and was maintained on this same immunodominant HLA subregion, which comprises only 20% of the HLA molecule, in a diverse group of HLA-A∗01:01-mismatched transplant recipients. Thus, the B cell and antibody alloresponses appear tightly focused on a topographically defined region on the HLA-A∗01:01 crown that is conserved across individuals expressing distinct constellations of self-HLA-A.
针对人类白细胞抗原（HLA）蛋白的供体特异性抗体反应在移植供体和受体之间不匹配导致同种异体移植物损失，然而同种异体反应性B细胞和抗体靶向的HLA结构表位在很大程度上仍未确定。我们分析了HLA-A∗01:01-特异性B细胞在接受抗体介导排斥的移植肾和血液中的反应，并鉴定了免疫优势B细胞和抗体反应，这些反应出现在同种免疫反应的早期。这些反应主要集中在沿着HLA- a肽结合槽的α螺旋上的地形暴露的不匹配HLA残基上。我们证明，在不同的HLA- a∗01:01不匹配的移植受者群体中，抗HLA- a * 01:01 B细胞的同种异体反应融合并维持在相同的免疫优势HLA亚区，该亚区仅占HLA分子的20%。因此，B细胞和抗体同种异体反应似乎紧密地集中在HLA-A * 01:01冠上的一个地形上确定的区域，该区域在表达不同的自我HLA-A星座的个体中是保守的。
{"title":"Topography of the HLA-A protein enforces shared and convergent immunodominant B cell and antibody alloresponses in transplant recipients","authors":"John T. Killian, R. Glenn King, Aaron C.K. Lucander, James L. Kizziah, Christopher F. Fucile, Ruben Diaz-Avalos, Shihong Qiu, Aaron Silva-Sanchez, Betty J. Mousseau, Kevin J. Macon, Amanda R. Callahan, Guang Yang, M. Emon Hossain, Jobaida Akther, Daryl B. Good, Susan Kelso, Julie A. Houp, Frida Rosenblum, Paige M. Porrett, Song C. Ong, Frances E. Lund","doi":"10.1016/j.immuni.2025.10.014","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.10.014","url":null,"abstract":"Donor-specific antibody responses against human leukocyte antigen (HLA) proteins mismatched between transplant donors and recipients cause allograft loss, yet the structural HLA epitopes targeted by alloreactive B cells and antibodies remain largely unresolved. We profiled the HLA-A<sup>∗</sup>01:01-specific B cell response in the transplanted kidney and blood of a recipient undergoing antibody-mediated rejection and identified immunodominant B cell and antibody responses that emerged early in the alloimmune response. These responses were focused on topographically exposed mismatched HLA residues located in the α helices along the peptide-binding groove of HLA-A<sup>∗</sup>01:01. We demonstrated that the anti-HLA-A<sup>∗</sup>01:01 B cell alloresponse converged and was maintained on this same immunodominant HLA subregion, which comprises only 20% of the HLA molecule, in a diverse group of HLA-A<sup>∗</sup>01:01-mismatched transplant recipients. Thus, the B cell and antibody alloresponses appear tightly focused on a topographically defined region on the HLA-A<sup>∗</sup>01:01 crown that is conserved across individuals expressing distinct constellations of self-HLA-A.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"362 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145583754","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 : 2025-11-21DOI: 10.1016/j.immuni.2025.10.021
Sofía Castelli, Wesley V. Wilson, Ugur Uslu, Amanda V. Finck, Philipp C. Rommel, Charles-Antoine Assenmacher, Sebastian J. Atoche, Mikko Siurala, M. Angela Aznar, Regina M. Young, Carl H. June
The success of chimeric antigen receptor (CAR) T cell therapies targeting solid tumors is limited by the immunosuppressive tumor microenvironment. We demonstrate that endowing CAR T cells with ectopic interleukin (IL)-9 signaling by co-expressing an IL-9 receptor rewires CAR T cell fate under antigen stress to enhance antitumor efficacy. In preclinical solid tumor models, IL-9-signaling CAR T cells exhibit increased expansion, persistence, and tumor infiltration, resulting in superior tumor control at substantially lower doses than conventional products. Trajectory and RNA velocity analyses of single-cell RNA sequencing data reveal that IL-9 signaling alters CAR T cell differentiation under antigen stress away from dysfunction, favoring a multipotent transition toward CD8+ T cell memory and effector states and promoting a CD4+ cell proliferative state. Interrogation of transcription factor pathways indicates that IL-9-mediated activation of STAT1 and STAT4 may contribute to the superior phenotype of IL-9-signaling CAR T cells, providing a promising therapeutic strategy for targeting solid cancers.
{"title":"IL-9 signaling redirects CAR T cell fate toward CD8+ memory and CD4+ cycling states, enhancing antitumor efficacy","authors":"Sofía Castelli, Wesley V. Wilson, Ugur Uslu, Amanda V. Finck, Philipp C. Rommel, Charles-Antoine Assenmacher, Sebastian J. Atoche, Mikko Siurala, M. Angela Aznar, Regina M. Young, Carl H. June","doi":"10.1016/j.immuni.2025.10.021","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.10.021","url":null,"abstract":"The success of chimeric antigen receptor (CAR) T cell therapies targeting solid tumors is limited by the immunosuppressive tumor microenvironment. We demonstrate that endowing CAR T cells with ectopic interleukin (IL)-9 signaling by co-expressing an IL-9 receptor rewires CAR T cell fate under antigen stress to enhance antitumor efficacy. In preclinical solid tumor models, IL-9-signaling CAR T cells exhibit increased expansion, persistence, and tumor infiltration, resulting in superior tumor control at substantially lower doses than conventional products. Trajectory and RNA velocity analyses of single-cell RNA sequencing data reveal that IL-9 signaling alters CAR T cell differentiation under antigen stress away from dysfunction, favoring a multipotent transition toward CD8<sup>+</sup> T cell memory and effector states and promoting a CD4<sup>+</sup> cell proliferative state. Interrogation of transcription factor pathways indicates that IL-9-mediated activation of STAT1 and STAT4 may contribute to the superior phenotype of IL-9-signaling CAR T cells, providing a promising therapeutic strategy for targeting solid cancers.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"1 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145560560","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 : 2025-11-21DOI: 10.1016/j.immuni.2025.10.024
Hua Jiang, Sam Limsuwannarot, Kayla R. Kulhanek, Aastha Pal, Ossama Labiad, Lea W. Rysavy, Ada Wong, Leon Su, Sarah Cavender, Johnathon Soro, Stefano Testa, Heather Ogana, Deepa Waghray, Pingdong Tao, Kevin M. Jude, Christopher S. Seet, Gay M. Crooks, Everett J. Moding, K. Christopher Garcia, Anusha Kalbasi
Cytokines and their receptors enable precise tuning of T cell function. Leveraging this biology holds tremendous promise for optimizing antitumor immunity. Arming T cells with a synthetically orthogonal interleukin (IL)-9 receptor (o9R), for instance, permits facile engraftment and potent anti-tumor functions. Exploiting the paucity of wild-type IL-9R expression and the safety of high doses of IL-9, here, we showed that, compared with o9R, T cells engineered with wild-type IL-9R exhibited superior tissue infiltration, stemness, and anti-tumor activity. These qualities were consistent with a stronger Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signal, which included canonically IL-12-driven STAT4 in addition to STAT1/3/5. IL-9R T cells were exquisitely sensitive to perturbations of proximal signaling, including structure-guided attenuation, amplification, and rebalancing of JAK/STAT signals. Biased IL-9R mutants showed that STAT1 acts as a rheostat between stem-like and effector states. In summary, we identify IL-9/IL-9R as a naturally orthogonal cytokine-receptor pair with an optimal JAK/STAT signaling profile for engineered T cell therapy.
{"title":"IL-9 as a naturally orthogonal cytokine with optimal JAK/STAT signaling for engineered T cell therapy","authors":"Hua Jiang, Sam Limsuwannarot, Kayla R. Kulhanek, Aastha Pal, Ossama Labiad, Lea W. Rysavy, Ada Wong, Leon Su, Sarah Cavender, Johnathon Soro, Stefano Testa, Heather Ogana, Deepa Waghray, Pingdong Tao, Kevin M. Jude, Christopher S. Seet, Gay M. Crooks, Everett J. Moding, K. Christopher Garcia, Anusha Kalbasi","doi":"10.1016/j.immuni.2025.10.024","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.10.024","url":null,"abstract":"Cytokines and their receptors enable precise tuning of T cell function. Leveraging this biology holds tremendous promise for optimizing antitumor immunity. Arming T cells with a synthetically orthogonal interleukin (IL)-9 receptor (o9R), for instance, permits facile engraftment and potent anti-tumor functions. Exploiting the paucity of wild-type IL-9R expression and the safety of high doses of IL-9, here, we showed that, compared with o9R, T cells engineered with wild-type IL-9R exhibited superior tissue infiltration, stemness, and anti-tumor activity. These qualities were consistent with a stronger Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signal, which included canonically IL-12-driven STAT4 in addition to STAT1/3/5. IL-9R T cells were exquisitely sensitive to perturbations of proximal signaling, including structure-guided attenuation, amplification, and rebalancing of JAK/STAT signals. Biased IL-9R mutants showed that STAT1 acts as a rheostat between stem-like and effector states. In summary, we identify IL-9/IL-9R as a naturally orthogonal cytokine-receptor pair with an optimal JAK/STAT signaling profile for engineered T cell therapy.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"105 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145560557","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 : 2025-11-17DOI: 10.1016/j.immuni.2025.10.022
Emily R. Siniscalco, Hailong Meng, Gisela Gabernet, Gaspar. A. Pacheco, Shahab Saghaei, Sydney I. Ramirez, L. Benjamin Hills, Farhoud Faraji, Shuting Chen, Xiangyun Yin, Christine Dien, Laura R. Hoyt, Elise G. Liu, Abel Barrett, Neima Briggs, Adam Williams, Vipul Shukla, Shane Crotty, Duane R. Wesemann, Steven H. Kleinstein, Stephanie C. Eisenbarth
Immunoglobulin (Ig)A is the primary isotype protecting the gut barrier, yet fundamental aspects of antigen-specific IgA induction remain unknown. Gut lymphoid organs are chronically exposed to foreign antigens, are structurally different from other lymphoid tissues, and are functionally unique. This suggests gut IgA induction occurs through noncanonical means. Indeed, we observed the generation of affinity-matured IgA B cells through both germinal center (GC) and nonGC pathways. Although most antibody isotypes are generated directly from naive IgM B cells, we discovered that IgG1 GC B cells can generate gut mucosal IgA in mice, with a similar relationship in mucosal and non-mucosal sites in humans. This supports a model of IgA generation through sequential class switching, linking the specificity of mucosal IgA and systemic IgG1 humoral immunity to gut-derived antigens. Defining these pathways is essential for the design of mucosal vaccines, which need to generate IgA and IgG antibodies for efficient barrier and systemic protection.
{"title":"Sequential class switching generates antigen-specific gut IgA from IgG1 B cells","authors":"Emily R. Siniscalco, Hailong Meng, Gisela Gabernet, Gaspar. A. Pacheco, Shahab Saghaei, Sydney I. Ramirez, L. Benjamin Hills, Farhoud Faraji, Shuting Chen, Xiangyun Yin, Christine Dien, Laura R. Hoyt, Elise G. Liu, Abel Barrett, Neima Briggs, Adam Williams, Vipul Shukla, Shane Crotty, Duane R. Wesemann, Steven H. Kleinstein, Stephanie C. Eisenbarth","doi":"10.1016/j.immuni.2025.10.022","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.10.022","url":null,"abstract":"Immunoglobulin (Ig)A is the primary isotype protecting the gut barrier, yet fundamental aspects of antigen-specific IgA induction remain unknown. Gut lymphoid organs are chronically exposed to foreign antigens, are structurally different from other lymphoid tissues, and are functionally unique. This suggests gut IgA induction occurs through noncanonical means. Indeed, we observed the generation of affinity-matured IgA B cells through both germinal center (GC) and nonGC pathways. Although most antibody isotypes are generated directly from naive IgM B cells, we discovered that IgG1 GC B cells can generate gut mucosal IgA in mice, with a similar relationship in mucosal and non-mucosal sites in humans. This supports a model of IgA generation through sequential class switching, linking the specificity of mucosal IgA and systemic IgG1 humoral immunity to gut-derived antigens. Defining these pathways is essential for the design of mucosal vaccines, which need to generate IgA and IgG antibodies for efficient barrier and systemic protection.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"33 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145531629","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 : 2025-11-13DOI: 10.1016/j.immuni.2025.10.020
Jennifer M. Umhoefer, Maya M. Arce, Sivakanthan Kasinathan, Sean Whalen, Rama Dajani, Sanjana Subramanya, Laine Goudy, Julia A. Belk, Royce Zhou, Minh T.N. Pham, Wenxi Zhang, Rosmely Hernandez, Carinna Tran, Nikhita Kirthivasan, Jacob W. Freimer, Cody T. Mowery, Vinh Nguyen, Mineto Ota, Benjamin G. Gowen, Dimitre R. Simeonov, Alexander Marson
FOXP3 is a lineage-defining transcription factor (TF) for immune-suppressive regulatory T cells (Treg cells). Although mice exclusively express FOXP3 in Treg cells, stimulated conventional CD4+ T cells (Tconv cells) also transiently express FOXP3 in humans. Mechanisms governing these distinct expression patterns need elucidation. Here, we performed CRISPR screens tiling the FOXP3 locus and targeting TFs in human Treg and Tconv cells to identify cis-regulatory elements (CREs) and trans-regulators of FOXP3. Tconv cell FOXP3 expression depended on a subset of Treg cell CREs, as well as Tconv-cell-selective positive (NS+) and negative (NS−) CREs. Combinatorial silencing of Tconv cell CREs revealed their epistatic logic. These CREs are occupied and regulated by TFs that we identified as FOXP3 regulators. Finally, mutagenesis of murine NS− CRE revealed its essentiality for restricting FOXP3 expression to Treg cells. We map CRE and TF circuitry to reveal distinct cell- and species-specific regulation of FOXP3 expression.
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