{"title":"A LAGging kiss leaves T cells cold","authors":"Thomas T. Xu, Shiv Pillai","doi":"10.1126/sciimmunol.aea8744","DOIUrl":"10.1126/sciimmunol.aea8744","url":null,"abstract":"<div >LAG-3 dampens CD4+ T cell activation by disrupting CDε-Lck condensates and is a therapeutic target in both cancer and autoimmunity.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 110","pages":""},"PeriodicalIF":16.3,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144758629","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}
Nicole Almanzar, Daping Yang, Jingya Xia, Swalpa Udit, Prabhu Joshi, Sandeep Adhikari, Daisy A. Hoagland, Stephen T. Yeung, Camille Khairallah, Tomas Huerta, Antonia Wallrapp, Benjamin D. Umans, Nicole Sarden, Ozge Erdogan, Nadia Baalbaki, Jiawei Hou, Anna Beekmayer-Dhillon, Juhyun Lee, Kimberly A. Meerschaert, Stephen D. Liberles, Ruth A. Franklin, Bryan G. Yipp, Kamal M. Khanna, Pankaj Baral, Adam L. Haber, Isaac M. Chiu
{"title":"Vagal TRPV1+ sensory neurons protect against influenza virus infection by regulating lung myeloid cell dynamics","authors":"Nicole Almanzar, Daping Yang, Jingya Xia, Swalpa Udit, Prabhu Joshi, Sandeep Adhikari, Daisy A. Hoagland, Stephen T. Yeung, Camille Khairallah, Tomas Huerta, Antonia Wallrapp, Benjamin D. Umans, Nicole Sarden, Ozge Erdogan, Nadia Baalbaki, Jiawei Hou, Anna Beekmayer-Dhillon, Juhyun Lee, Kimberly A. Meerschaert, Stephen D. Liberles, Ruth A. Franklin, Bryan G. Yipp, Kamal M. Khanna, Pankaj Baral, Adam L. Haber, Isaac M. Chiu","doi":"10.1126/sciimmunol.ads6243","DOIUrl":"10.1126/sciimmunol.ads6243","url":null,"abstract":"<div >Influenza viruses are a major global cause of morbidity and mortality. Although vagal TRPV1<sup>+</sup> nociceptive sensory neurons are known to mediate defenses against harmful agents, including pathogens, their function in lung antiviral defenses remains unclear. Our study demonstrates that both systemic and vagal-specific ablation of TRPV1<sup>+</sup> nociceptors reduce survival in mice infected with influenza A virus (IAV). Despite no difference in viral load, mice lacking TRPV1<sup>+</sup> neurons exhibited increased viral spread, exacerbated lung pathology, and elevated levels of proinflammatory cytokines. Loss of TRPV1<sup>+</sup> neurons altered the lung immune landscape, including an expansion of neutrophils and monocyte-derived macrophages. Transcriptional analysis revealed impaired interferon signaling in myeloid cells and an imbalance in distinct neutrophil subpopulations in the absence of nociceptors. Furthermore, antibody-mediated depletion of myeloid cells during IAV infection substantially improved survival after nociceptor ablation, underscoring the role of TRPV1<sup>+</sup> neurons in preventing pathogenic myeloid cell states that contribute to IAV-induced mortality.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 110","pages":""},"PeriodicalIF":16.3,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.ads6243","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144756483","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}
{"title":"Human CD4+ T cells regulate peripheral immune responses in rheumatoid arthritis via insulin-like growth factor–like family member 2","authors":"Akinori Murakami, Rinko Akamine, Shiro Tanaka, Koichi Murata, Kohei Nishitani, Hiromu Ito, Ryu Watanabe, Takayuki Fujii, Takeshi Iwasaki, Yuki Masuo, Osamu Iri, Shinichiro Nakamura, Shinichi Kuriyama, Yugo Morita, Yasuhiro Murakawa, Chikashi Terao, Yukinori Okada, Motomu Hashimoto, Shuichi Matsuda, Hideki Ueno, Hiroyuki Yoshitomi","doi":"10.1126/sciimmunol.adr3838","DOIUrl":"10.1126/sciimmunol.adr3838","url":null,"abstract":"<div >Human CD4<sup>+</sup> T cells play a central role in the pathogenesis of autoimmune diseases, but their immunoregulatory mechanisms driving pathogenesis remain to be elucidated. We show that human T peripheral helper cells (T<sub>PH</sub> cells) regulate peripheral immune responses via insulin-like growth factor–like family member 2 (IGFL2), an inflammatory factor found exclusively in primates. Single-cell RNA sequencing of seropositive rheumatoid arthritis (RA) synovium showed that <i>IGFL2</i> is specifically expressed by CD4<sup>+</sup> T cells, predominantly T<sub>PH</sub> cells. IGFL2 promotes transforming growth factor–β–induced CXCL13 production in CD4<sup>+</sup> T cells, activates nuclear factor κB signaling, and induces monocyte gene signatures like those of pathogenic macrophages. CRISPR-Cas9 knockout of IGFL2 in synovial T<sub>PH</sub> cells suppressed this gene signature in cocultured monocytes. Blood IGFL2 protein levels correlated with RA disease severity and could be used as a potential biomarker. These findings highlight the involvement of IGFL2 in RA pathogenesis, emphasizing how human T<sub>PH</sub> cells regulate local immune responses via IGFL2.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 110","pages":""},"PeriodicalIF":16.3,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144756484","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}
Nathan W. Zammit, Ariana Vargas-Castillo, P. Kent Langston, Gang Wang, Yangzhong Zhou, Bruce M. Spiegelman, Christophe Benoist, Diane Mathis
{"title":"Regulatory T cells in brown adipose tissue safeguard thermogenesis by restraining interferon-γ–producing lymphocytes","authors":"Nathan W. Zammit, Ariana Vargas-Castillo, P. Kent Langston, Gang Wang, Yangzhong Zhou, Bruce M. Spiegelman, Christophe Benoist, Diane Mathis","doi":"10.1126/sciimmunol.ads0478","DOIUrl":"10.1126/sciimmunol.ads0478","url":null,"abstract":"<div >Whereas visceral adipose tissue (VAT) primarily stores excess energy, brown adipose tissue (BAT) dissipates it in a process termed nonshivering thermogenesis. Several key VAT features, particularly murine epidydimal VAT, are regulated by a distinct population of regulatory T (T<sub>reg</sub>) cells, raising the question of whether BAT hosts an analogous population. Although T<sub>reg</sub> cells have been observed in BAT, their properties and mechanisms of action require elucidation. We found BAT T<sub>reg</sub> cells to be heterogeneous in subtissular localization and subtype composition. Punctual depletion of T<sub>reg</sub> cells unleashed interferon-γ (IFN-γ)–producing lymphocytes in BAT, but not in subcutaneous or visceral fat depots, leading to IFN-γ–dependent mitochondrial dysfunction and metabolic dysregulation, thereby impeding nonshivering thermogenesis. Cold challenge selectively expanded the IL-18R1<sup>+</sup> T<sub>reg</sub> subtype in BAT; stripping this receptor specifically from T<sub>reg</sub> cells unleashed IFN-γ–producing lymphocytes and compromised temperature control. Thus, control of local IFN-γ production is a core feature of T<sub>reg</sub> cell control of tissue homeostasis.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 109","pages":""},"PeriodicalIF":17.6,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.ads0478","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144705732","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}
Julia Niessl, Thomas R. Müller, Christian Constantz, Curtis Cai, Vera Nilsén, Olga Rivera Ballesteros, Sarah Adamo, Tobias Kammann, Elli Mouchtaridi, Yu Gao, Mily Akhirunnesa, Elisa J. M. Raineri, Whitney Weigel, Efthymia Kokkinou, Christopher Stamper, Anne Marchalot, John Bassett, Sabrina Ferreira, Inga Rodahl, Nicole Wild, Teresa Stellaccio, Demi Brownlie, Emma Ringqvist, Malin Flodström-Tullberg, Sian Llewellyn-Lacey, Chris Tibbitt, Quirin Hammer, Jakob Michaëlsson, David A. Price, Jenny Mjösberg, Nicole Marquardt, Johan K. Sandberg, Takuya Sekine, Carl Jorns, Marcus Buggert
{"title":"Tissue origin and virus specificity shape human CD8+ T cell cytotoxicity","authors":"Julia Niessl, Thomas R. Müller, Christian Constantz, Curtis Cai, Vera Nilsén, Olga Rivera Ballesteros, Sarah Adamo, Tobias Kammann, Elli Mouchtaridi, Yu Gao, Mily Akhirunnesa, Elisa J. M. Raineri, Whitney Weigel, Efthymia Kokkinou, Christopher Stamper, Anne Marchalot, John Bassett, Sabrina Ferreira, Inga Rodahl, Nicole Wild, Teresa Stellaccio, Demi Brownlie, Emma Ringqvist, Malin Flodström-Tullberg, Sian Llewellyn-Lacey, Chris Tibbitt, Quirin Hammer, Jakob Michaëlsson, David A. Price, Jenny Mjösberg, Nicole Marquardt, Johan K. Sandberg, Takuya Sekine, Carl Jorns, Marcus Buggert","doi":"10.1126/sciimmunol.adq4881","DOIUrl":"10.1126/sciimmunol.adq4881","url":null,"abstract":"<div >CD8<sup>+</sup> T cells are classically defined by cytotoxic activity, but it has remained unclear whether cytotoxic programs are compartmentalized across tissues and memory subsets. Here, we established a human organ donor cohort and found that expression of conventional cytotoxic molecules—granulysin, perforin, and granzyme B—was most prominent among circulating memory CD8<sup>+</sup> T cells and decreased progressively with tissue residency, inversely mirroring the expression of CD69 and CD103. Other cytotoxic molecules, including granzymes A, H, K, and M, were variably expressed across tissues, and memory CD8<sup>+</sup> T cells targeting persistent viruses expressed multiple granzymes coordinately. In an in vitro tonsil system, transforming growth factor–β induced discordant regulation of cytotoxic molecules and CD103. Combined with interleukin-15, this circuitry modulated proliferation and the acquisition of redirected killing activity via perforin and granzyme B. Our findings suggest that human memory CD8<sup>+</sup> T cell cytotoxicity is intricately regulated by environmental cues reflecting tissue location and antigen specificity.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 109","pages":""},"PeriodicalIF":17.6,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144657797","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}
Nagisa Yoshida, Anna Appios, Qian Li, Joseph P. Hutton, George Wood, Martin Potts, Julia Aleksandrowicz, Enrico R. Barrozo, Freya Dover, Holly Anderson, Katie Stephens, Irving L. M. H. Aye, Jake R. Thomas, Hannah C. M. Schenk, Adam M. Bourke, Catherine E. Aiken, Ashley Moffett, Andrew Sharkey, Anna V. Protasio, Kjersti M. Aagaard, James R. Edgar, Betty Y. W. Chung, Naomi McGovern
{"title":"Interactions between placental Hofbauer cells and L. monocytogenes change throughout gestation","authors":"Nagisa Yoshida, Anna Appios, Qian Li, Joseph P. Hutton, George Wood, Martin Potts, Julia Aleksandrowicz, Enrico R. Barrozo, Freya Dover, Holly Anderson, Katie Stephens, Irving L. M. H. Aye, Jake R. Thomas, Hannah C. M. Schenk, Adam M. Bourke, Catherine E. Aiken, Ashley Moffett, Andrew Sharkey, Anna V. Protasio, Kjersti M. Aagaard, James R. Edgar, Betty Y. W. Chung, Naomi McGovern","doi":"10.1126/sciimmunol.adq3066","DOIUrl":"10.1126/sciimmunol.adq3066","url":null,"abstract":"<div >Hofbauer cells (HBCs) are extraembryonic macrophages generated de novo within the human placenta. In this study, we explored how the properties of HBCs change throughout gestation. Our analysis revealed transcriptomic differences between first-trimester and term HBCs, with many of the altered genes linked to immune responses. As pregnancy progresses, HBCs exhibit a marked decrease in phagosome maturation and acidification. We show that the differences between first-trimester and term HBCs are important in the context of infection with <i>Listeria monocytogenes</i>, a pathogen that crosses the placenta and replicates within macrophages. Specifically, we observed reduced colony-forming units and diminished actin recruitment by <i>L. monocytogenes</i> in first-trimester HBCs compared with term HBCs. Our findings indicate that the ability of <i>L. monocytogenes</i> to escape from vacuoles is impaired within first-trimester HBCs. Thus, the changes in HBC biology across pregnancy are important in shaping their interactions with <i>L. monocytogenes.</i></div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 109","pages":""},"PeriodicalIF":17.6,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adq3066","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144657779","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}
{"title":"OTUD3 prevents ulcerative colitis by inhibiting microbiota-mediated STING activation","authors":"Bo Li, Taiki Sakaguchi, Haruka Tani, Takayoshi Ito, Mari Murakami, Ryu Okumura, Masao Kobayashi, Daisuke Okuzaki, Daisuke Motooka, Hiroki Ikeuchi, Takayuki Ogino, Tsunekazu Mizushima, Seiichi Hirota, Yuriko Otake-Kasamoto, Toshihiro Kishikawa, Shota Nakamura, Kouji Kobiyama, Ken J. Ishii, Takao Hashiguchi, Taro Kawai, Etsushi Kuroda, Shinichiro Shinzaki, Wataru Ise, Tomohiro Kurosaki, Akira Kikuchi, Yoshihiko Tomofuji, Yukinori Okada, Kiyoshi Takeda, Hisako Kayama","doi":"10.1126/sciimmunol.adm6843","DOIUrl":"10.1126/sciimmunol.adm6843","url":null,"abstract":"<div >Ulcerative colitis (UC) develops through a complicated interaction between the host and microbiota. Intestinal fibroblasts are believed to play crucial roles in the pathogenesis of UC, but the influence of the host-microbiota interaction on the pathophysiology of intestinal fibroblasts remains poorly understood. Here, we demonstrate that OTU deubiquitinase 3 (OTUD3) suppresses pathologic activation of fibroblasts exposed to microbial cyclic GMP-AMP (3′3’-cGAMP) in the colon by deubiquitinating stimulator of interferon genes (STING). Mice harboring a UC risk missense variant in the <i>Otud3</i> gene showed pathological features of UC in the colon after transplantation of a fecal microbiota with the potential to produce excessive cGAMP from patients with UC. Collectively, these results highlight a mechanism of the interaction between OTUD3 in host fibroblasts and STING-activating microbiota in UC development.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 109","pages":""},"PeriodicalIF":17.6,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144657759","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}
Chrysa Kapeni, Louise O’Brien, Dilyara Sabirova, Oliver Cast, Valentina Carbonaro, Stephen Clark-Leonard, Anne C. Machel, Flavio Beke, Sarah McDonald, Kate Fife, Maike de la Roche
{"title":"Noncanonical Hedgehog signaling through Smoothened controls cytotoxic T cell migration in the tumor microenvironment","authors":"Chrysa Kapeni, Louise O’Brien, Dilyara Sabirova, Oliver Cast, Valentina Carbonaro, Stephen Clark-Leonard, Anne C. Machel, Flavio Beke, Sarah McDonald, Kate Fife, Maike de la Roche","doi":"10.1126/sciimmunol.adr3127","DOIUrl":"10.1126/sciimmunol.adr3127","url":null,"abstract":"<div >The Hedgehog (Hh) signaling pathway is aberrantly regulated in cancer. Hh inhibitors are successful in treating basal cell carcinoma (BCC) and Sonic Hedgehog–driven medulloblastoma but have largely failed in clinical trials of other solid cancers. We show that Hh inhibitor treatment specifically diminishes CD8 T cell migration into the tumor microenvironment, both in murine cancer models and resected BCCs from patients treated with the Smoothened (Smo) inhibitor vismodegib. Using small-molecule antagonists and genetic knockout models of key Hh signaling components, we demonstrate that the migration defect is mediated exclusively by the signal transducer Smo and not Hh ligands or Gli transcription factors. Smo acts noncanonically as a G protein–coupled receptor to regulate the migration of murine and human CD8 T cells via RhoA. Our data establish a link between Hh inhibition in vivo and the antitumor immune response and provide the basis for improved Hh targeting approaches for patients with cancer.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 109","pages":""},"PeriodicalIF":17.6,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144604051","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}
Xianwei Wang, Jiarui Li, Lucas Rebuffet, Ming Cheng, Boqun Bao, Yawen Chen, Xiaodong Zheng, Yongyan Chen, Haoyu Sun, Rui Sun, Eric Vivier, Hui Peng, Zhigang Tian
{"title":"Innate lymphoid cells originate from fetal liver–derived tissue-resident progenitors","authors":"Xianwei Wang, Jiarui Li, Lucas Rebuffet, Ming Cheng, Boqun Bao, Yawen Chen, Xiaodong Zheng, Yongyan Chen, Haoyu Sun, Rui Sun, Eric Vivier, Hui Peng, Zhigang Tian","doi":"10.1126/sciimmunol.adu7962","DOIUrl":"10.1126/sciimmunol.adu7962","url":null,"abstract":"<div >Committed progenitors with innate lymphoid cell (ILC) developmental potential are present in the fetus and bone marrow (BM). However, how fetal and BM hematopoiesis temporally and spatially contribute to ILC pools remains unclear. Here, we elucidated the distinct origins and developmental pathways of extramedullary and intramedullary ILCs in mice during ontogeny. ILC-restricted hematopoiesis is initiated in the fetal liver (FL), and then FL-derived PD-1<sup>+</sup> ILC precursors (ILCPs) seed fetal lung and intestine. Organ niches determine the commitment of ILCPs to downstream precursors, including bipotent ILC1-ILC3 precursors (ILC1/3Ps), which preferentially reside in the liver and intestine, and ILC2 precursors (ILC2Ps), which are found predominantly in the lung. These precursors persist in adulthood and contribute to local ILC pools in a BM-independent manner. In contrast, intramedullary ILC2Ps and ILC2s rely on BM hematopoiesis. Thus, our study demonstrates that extramedullary and intramedullary ILCs have different origins and provides a comprehensive framework for ILC developmental dynamics.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 109","pages":""},"PeriodicalIF":17.6,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144604052","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}
Arja Ray, Molly Bassette, Kenneth H. Hu, Lomax F. Pass, Tristan Courau, Bushra Samad, Alexis J. Combes, Vrinda Johri, Brittany Davidson, Katherine Wai, Patrick Ha, Grace Hernandez, Itzia Zaleta-Linares, Matthew F. Krummel
{"title":"Multimodal delineation of a layer of effector function among exhausted CD8 T cells in tumors","authors":"Arja Ray, Molly Bassette, Kenneth H. Hu, Lomax F. Pass, Tristan Courau, Bushra Samad, Alexis J. Combes, Vrinda Johri, Brittany Davidson, Katherine Wai, Patrick Ha, Grace Hernandez, Itzia Zaleta-Linares, Matthew F. Krummel","doi":"10.1126/sciimmunol.adt3537","DOIUrl":"10.1126/sciimmunol.adt3537","url":null,"abstract":"<div >Undescribed functional axes may intersect with the trajectory of T cell exhaustion (T<sub>EX</sub>) to contribute to the antitumoral functions of CD8 T cells. By leveraging fluorescent transcriptional reporting of the T cell activation marker <i>Cd69</i>, we defined a classifier for potent versus suboptimal CD69<sup>+</sup> activation states arising from T cell stimulation. In tumors, this delineation provided an additional functional readout among T<sub>EX</sub> subsets, marked by enhanced effector molecule production. The more potent <i>Cd69</i>-TFP<sup>hi</sup> state was the most prominent in a T cell–mediated tumor clearance model, displaying increased engagement and superior tumor cell killing. Simultaneous analysis of gene and protein expression in human head and neck tumors enabled a similar strategy to identify <i>Cd69</i>RNA<sup>hi</sup>CD69<sup>+</sup> cells with enhanced functional features compared with <i>Cd69</i>RNA<sup>lo</sup>CD69<sup>+</sup> cells among intratumoral CD8 T cell subsets. Thus, refining the T cell functional landscape in tumors potentiates the identification of rare, potent effectors that could be leveraged for improving cancer treatment.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 109","pages":""},"PeriodicalIF":17.6,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144604053","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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