Pub Date : 2025-11-03DOI: 10.1016/j.immuni.2025.10.012
Deepika Sharma, Ankit Malik, Veronica Locher, Shaina McGrath, Sarah Zabala, Hardik Grover, Cezary Ciszewski, Li Chen, Daping Yang, Isaac M. Chiu, Bana Jabri
Deciphering multicellular interactions is essential to understanding immune-mediated diseases. Myeloid cells can coordinate inflammatory responses and are central to immune crosstalk with neuronal, epithelial, and stromal cells. Here, we show that myeloid-specific loss of ten-eleven-translocation methylcytosine dioxygenase 2 (TET2) protected against colitis by limiting enterochromaffin (EC) cell differentiation and subsequent serotonin release. This protective effect was mediated by elevated interleukin (IL)-1β production by myeloid cells, which signals to tyrosine hydroxylase (TH)-positive neurons under inflammatory conditions. Neuronal IL-1R signaling dampened neuronal-epithelial interactions and consequent α₁-adrenergic signaling, thereby reducing EC differentiation. Conversely, physiological stress exacerbated colitis by enhancing catecholaminergic signals, which increased EC differentiation and serotonin production following mucosal injury. Thus, myeloid-derived IL-1β and stress exert opposing control over colitis severity through the α₁-adrenergic-EC axis, uncovering a neuro-immune-epithelial circuit that shapes intestinal inflammation.
{"title":"A myeloid Tet2-IL-1β axis modulates intestinal inflammation by restricting catecholaminergic stimulation of enterochromaffin cell differentiation","authors":"Deepika Sharma, Ankit Malik, Veronica Locher, Shaina McGrath, Sarah Zabala, Hardik Grover, Cezary Ciszewski, Li Chen, Daping Yang, Isaac M. Chiu, Bana Jabri","doi":"10.1016/j.immuni.2025.10.012","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.10.012","url":null,"abstract":"Deciphering multicellular interactions is essential to understanding immune-mediated diseases. Myeloid cells can coordinate inflammatory responses and are central to immune crosstalk with neuronal, epithelial, and stromal cells. Here, we show that myeloid-specific loss of ten-eleven-translocation methylcytosine dioxygenase 2 (TET2) protected against colitis by limiting enterochromaffin (EC) cell differentiation and subsequent serotonin release. This protective effect was mediated by elevated interleukin (IL)-1β production by myeloid cells, which signals to tyrosine hydroxylase (TH)-positive neurons under inflammatory conditions. Neuronal IL-1R signaling dampened neuronal-epithelial interactions and consequent α₁-adrenergic signaling, thereby reducing EC differentiation. Conversely, physiological stress exacerbated colitis by enhancing catecholaminergic signals, which increased EC differentiation and serotonin production following mucosal injury. Thus, myeloid-derived IL-1β and stress exert opposing control over colitis severity through the α₁-adrenergic-EC axis, uncovering a neuro-immune-epithelial circuit that shapes intestinal inflammation.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"156 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145427924","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 : 2025-11-03DOI: 10.1016/j.immuni.2025.10.004
Annabell Bachem, Michele Clarke, Geraldine Kong, Ilaryia Tarasova, Lachlan Dryburgh, Lindsay Kosack, Ariane R. Lee, Lewis D. Newland, Teagan Wagner, Emma Bawden, Kah Min Yap, Michael D. Wilson, Sven Engel, Kayla R. Wilson, Brendan E. Russ, Kshitij Tandon, Peter Kar Han Lau, Grant McArthur, Vanessa R. Marcelino, Paul A. Beavis, Sammy Bedoui
A range of microbiota species correlate with improved cancer outcomes in patients and confer protection in pre-clinical mouse models. Here, we examined how microbiota regulate CD8+ T cell immunity against melanoma. Spontaneous control of cutaneous melanoma in mice correlated with metabolic pathways required for microbial synthesis of short-chain fatty acids (SCFAs) shared between several microbiota species. Diet-induced enforcement of SCFA production by the gut microbiota reduced melanoma progression and enriched tumor-specific stem-like CD127+CD8+ T cells in the tumor-draining lymph node (tdLN). The SCFA butyrate induced a FOXO1-driven stemness program and directly promoted the differentiation of tumor-specific CD127+CD8+ T cells in the tdLN. Metabolic flux modeling predicted enhanced microbial production of butyrate in melanoma patients with complete therapeutic responses to immune checkpoint blockade (ICB), and butyrate induced transcriptional features of ICB responsiveness in CD8+ T cells. Our findings suggest a critical role for metabolite production shared across several microbiota species in the preservation of stem-like tumor-specific CD8+ T cells.
{"title":"Microbiota-derived butyrate promotes a FOXO1-induced stemness program and preserves CD8+ T cell immunity against melanoma","authors":"Annabell Bachem, Michele Clarke, Geraldine Kong, Ilaryia Tarasova, Lachlan Dryburgh, Lindsay Kosack, Ariane R. Lee, Lewis D. Newland, Teagan Wagner, Emma Bawden, Kah Min Yap, Michael D. Wilson, Sven Engel, Kayla R. Wilson, Brendan E. Russ, Kshitij Tandon, Peter Kar Han Lau, Grant McArthur, Vanessa R. Marcelino, Paul A. Beavis, Sammy Bedoui","doi":"10.1016/j.immuni.2025.10.004","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.10.004","url":null,"abstract":"A range of microbiota species correlate with improved cancer outcomes in patients and confer protection in pre-clinical mouse models. Here, we examined how microbiota regulate CD8<sup>+</sup> T cell immunity against melanoma. Spontaneous control of cutaneous melanoma in mice correlated with metabolic pathways required for microbial synthesis of short-chain fatty acids (SCFAs) shared between several microbiota species. Diet-induced enforcement of SCFA production by the gut microbiota reduced melanoma progression and enriched tumor-specific stem-like CD127<sup>+</sup>CD8<sup>+</sup> T cells in the tumor-draining lymph node (tdLN). The SCFA butyrate induced a FOXO1-driven stemness program and directly promoted the differentiation of tumor-specific CD127<sup>+</sup>CD8<sup>+</sup> T cells in the tdLN. Metabolic flux modeling predicted enhanced microbial production of butyrate in melanoma patients with complete therapeutic responses to immune checkpoint blockade (ICB), and butyrate induced transcriptional features of ICB responsiveness in CD8<sup>+</sup> T cells. Our findings suggest a critical role for metabolite production shared across several microbiota species in the preservation of stem-like tumor-specific CD8<sup>+</sup> T cells.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"80 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145427925","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 : 2025-10-31DOI: 10.1016/j.immuni.2025.10.009
Marina Terekhova, Pavla Bohacova, Maxim N. Artyomov
Aging is an essential aspect of human life, and studying its mechanisms is crucial for extending lifespan and improving quality of life. The immune system plays a central role in the onset of age-related diseases. Understanding the differences between healthy and dysfunctional aging provides key insights into the fundamental immune alternations that occur prior to the point where the system begins to fail. In this review, we explore current perspectives on human immune aging. We focus on changes in the composition of, and consequential functional effects within, the major immune compartments in both circulation and tissues. We discuss earlier findings obtained through flow cytometry, alongside more recent studies utilizing single-cell and advanced cytometry techniques. We highlight here how these methods complement each other and explore potential sources of discrepancies. Finally, we address the challenges that persist in the field of human immune aging.
{"title":"Human immune aging","authors":"Marina Terekhova, Pavla Bohacova, Maxim N. Artyomov","doi":"10.1016/j.immuni.2025.10.009","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.10.009","url":null,"abstract":"Aging is an essential aspect of human life, and studying its mechanisms is crucial for extending lifespan and improving quality of life. The immune system plays a central role in the onset of age-related diseases. Understanding the differences between healthy and dysfunctional aging provides key insights into the fundamental immune alternations that occur prior to the point where the system begins to fail. In this review, we explore current perspectives on human immune aging. We focus on changes in the composition of, and consequential functional effects within, the major immune compartments in both circulation and tissues. We discuss earlier findings obtained through flow cytometry, alongside more recent studies utilizing single-cell and advanced cytometry techniques. We highlight here how these methods complement each other and explore potential sources of discrepancies. Finally, we address the challenges that persist in the field of human immune aging.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"76 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145403930","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 : 2025-10-31DOI: 10.1016/j.immuni.2025.10.007
Zhimeng Wang, Yanfei Hou, Peiyuan Liu, Ruinan Wu, Jiaming Yang, Shilong Fan, Zexu Peng, Xiaoxu Han, Bin Su, Conggang Zhang
The cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS)-cyclic GMP-AMP (cGAMP)-stimulator of interferon genes (STING) pathway mediates antiviral innate immunity upon sensing cytosolic DNA. Here, we examined the impact of sphingomyelin phosphodiesterase acid-like 3B (SMPDL3B), a paralog of the LXR lipid metabolism-induced cGAMP-degrading enzyme SMPDL3A, on viral infection. We found that SMPDL3B was induced and stabilized by both viral infection and membrane-disturbing agents, suggesting a role in sensing membrane stress as an early signal of cellular danger. Deletion of SMPDL3B impaired DNA virus infection. Upon induction, SMPDL3B suppressed cGAS-STING signaling and downstream transcriptional pathways, including the interferon response. Mechanistically, SMPDL3B functioned as a cGAMP hydrolase; cGAMP-induced SMPDL3B dimerization enabled its hydrolase activity and a negative feedback loop that dampened STING signaling. SMPDL3B-deficient cells had elevated cGAMP concentrations, and Smpdl3b−/− mice exhibited enhanced cGAMP accumulation, heightened immune activation, and reduced viral loads upon herpes simplex virus type 1 (HSV-1) infection. Thus, SMPDL3B links membrane stress to modulation of cGAS-STING signaling through cGAMP degradation, with potential implications in the contexts of inflammation or autoimmunity.
{"title":"Membrane integrity changes upon viral infection activate sphingomyelinase SMPDL3B to restrict cGAS-STING signaling via cGAMP degradation","authors":"Zhimeng Wang, Yanfei Hou, Peiyuan Liu, Ruinan Wu, Jiaming Yang, Shilong Fan, Zexu Peng, Xiaoxu Han, Bin Su, Conggang Zhang","doi":"10.1016/j.immuni.2025.10.007","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.10.007","url":null,"abstract":"The cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS)-cyclic GMP-AMP (cGAMP)-stimulator of interferon genes (STING) pathway mediates antiviral innate immunity upon sensing cytosolic DNA. Here, we examined the impact of sphingomyelin phosphodiesterase acid-like 3B (SMPDL3B), a paralog of the LXR lipid metabolism-induced cGAMP-degrading enzyme SMPDL3A, on viral infection. We found that SMPDL3B was induced and stabilized by both viral infection and membrane-disturbing agents, suggesting a role in sensing membrane stress as an early signal of cellular danger. Deletion of SMPDL3B impaired DNA virus infection. Upon induction, SMPDL3B suppressed cGAS-STING signaling and downstream transcriptional pathways, including the interferon response. Mechanistically, SMPDL3B functioned as a cGAMP hydrolase; cGAMP-induced SMPDL3B dimerization enabled its hydrolase activity and a negative feedback loop that dampened STING signaling. SMPDL3B-deficient cells had elevated cGAMP concentrations, and <em>Smpdl3b</em><sup>−/−</sup> mice exhibited enhanced cGAMP accumulation, heightened immune activation, and reduced viral loads upon herpes simplex virus type 1 (HSV-1) infection. Thus, SMPDL3B links membrane stress to modulation of cGAS-STING signaling through cGAMP degradation, with potential implications in the contexts of inflammation or autoimmunity.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"150 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145403931","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 : 2025-10-31DOI: 10.1016/j.immuni.2025.10.011
Mariana C.G. Miranda-Waldetario, Edgar Gonzalez-Kozlova, Edenil C. Aguilar, Laura Xie, Kenneth B. Hoehn, Carlos J. Aranda, Yolanda Garcia-Carmona, Erica G.M. Ma, Emma S. Agudelo, Jamie Redes, Maria A. Curotto de Lafaille
Expression of the IgE BCR is associated with increased B cell apoptosis, yet in persistent allergy, sustained production of IgE antibodies in the absence of allergen exposure suggests the existence of long-lived IgE plasma cells (PCs). Here we studied the development and localization of IgE PCs in mouse models of allergy. After immunization, IgE PCs underwent maturation in spleen and lymph nodes, acquiring a stable MHCIIloCD93+CD98hiBCRlo phenotype. Mature IgE PCs had a distinct transcriptional profile adapted to high protein synthesis, glycosylation, and survival and resisted BCR-crosslinking-induced apoptosis. Immunization induced a burst of short-lived IgE PC formation, followed by a reduced differentiation rate over time, compared with IgG1 PCs. Timestamping of PCs revealed long-lived IgE PCs that localize to the spleen, in addition to the bone marrow (BM). Thus, immune challenge can generate both short-lived and long-lived IgE PCs, with long-lived IgE PCs in spleen and BM contributing to allergy persistence.
{"title":"Long-lived IgE plasma cells that reside in the spleen contribute to the persistence of the IgE response","authors":"Mariana C.G. Miranda-Waldetario, Edgar Gonzalez-Kozlova, Edenil C. Aguilar, Laura Xie, Kenneth B. Hoehn, Carlos J. Aranda, Yolanda Garcia-Carmona, Erica G.M. Ma, Emma S. Agudelo, Jamie Redes, Maria A. Curotto de Lafaille","doi":"10.1016/j.immuni.2025.10.011","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.10.011","url":null,"abstract":"Expression of the IgE BCR is associated with increased B cell apoptosis, yet in persistent allergy, sustained production of IgE antibodies in the absence of allergen exposure suggests the existence of long-lived IgE plasma cells (PCs). Here we studied the development and localization of IgE PCs in mouse models of allergy. After immunization, IgE PCs underwent maturation in spleen and lymph nodes, acquiring a stable MHCII<sup>lo</sup>CD93<sup>+</sup>CD98<sup>hi</sup>BCR<sup>lo</sup> phenotype. Mature IgE PCs had a distinct transcriptional profile adapted to high protein synthesis, glycosylation, and survival and resisted BCR-crosslinking-induced apoptosis. Immunization induced a burst of short-lived IgE PC formation, followed by a reduced differentiation rate over time, compared with IgG1 PCs. Timestamping of PCs revealed long-lived IgE PCs that localize to the spleen, in addition to the bone marrow (BM). Thus, immune challenge can generate both short-lived and long-lived IgE PCs, with long-lived IgE PCs in spleen and BM contributing to allergy persistence.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"32 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145403934","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 : 2025-10-31DOI: 10.1016/j.immuni.2025.10.001
Mingming Wu, Shiyue Yang, Zhentao Yang, Jian Fan, Shirley H. Lomeli, Prashanthi Dharanipragada, Gatien Moriceau, Robert Damoiseaux, Mark C. Kelley, Carlos N. Prieto-Granada, Alessio Giubellino, Mehdi Nosrati, Mohammed Kashani-Sabet, Kevin B. Kim, Douglas B. Johnson, Sixue Liu, Roger S. Lo
Patients who initially respond to immune checkpoint inhibitors (ICIs) often relapse. Here, we studied how disease-progressive (DP) clinical melanomas evolve genomically to acquire ICI resistance. Compared to patient-matched pretreatment tumors, DP tumors recurrently amplified and/or deleted anti-apoptotic and/or pro-apoptotic genes, respectively. By chronic exposure to killer T cells or ICI therapy, we derived acquired-resistant (AR) human melanoma cell lines and murine melanoma tumors that recapitulate co-occurrent copy-number variants (CNVs) of apoptotic genes observed in DP melanomas. AR and DP subclones expanded shared, private, and, in some subclones, preexistent driver CNVs. Compared to isogenic parental cells, AR melanoma cells attenuated apoptotic priming but, with overexpression of deleted pro-apoptotic genes, recovered mitochondrial priming and sensitivity to killer T cells or ICIs. In mice, pharmacologically reducing the apoptotic threshold of ICI persisters prevented relapses. Thus, CNVs can drive the evolution of resistance to ICIs in melanoma, with tumor cell-intrinsic apoptotic threshold representing a target to curtail persister evolution.
{"title":"Genomic copy-number variants drive apoptotic evasion underlying acquired resistance to immune checkpoint inhibitors","authors":"Mingming Wu, Shiyue Yang, Zhentao Yang, Jian Fan, Shirley H. Lomeli, Prashanthi Dharanipragada, Gatien Moriceau, Robert Damoiseaux, Mark C. Kelley, Carlos N. Prieto-Granada, Alessio Giubellino, Mehdi Nosrati, Mohammed Kashani-Sabet, Kevin B. Kim, Douglas B. Johnson, Sixue Liu, Roger S. Lo","doi":"10.1016/j.immuni.2025.10.001","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.10.001","url":null,"abstract":"Patients who initially respond to immune checkpoint inhibitors (ICIs) often relapse. Here, we studied how disease-progressive (DP) clinical melanomas evolve genomically to acquire ICI resistance. Compared to patient-matched pretreatment tumors, DP tumors recurrently amplified and/or deleted anti-apoptotic and/or pro-apoptotic genes, respectively. By chronic exposure to killer T cells or ICI therapy, we derived acquired-resistant (AR) human melanoma cell lines and murine melanoma tumors that recapitulate co-occurrent copy-number variants (CNVs) of apoptotic genes observed in DP melanomas. AR and DP subclones expanded shared, private, and, in some subclones, preexistent driver CNVs. Compared to isogenic parental cells, AR melanoma cells attenuated apoptotic priming but, with overexpression of deleted pro-apoptotic genes, recovered mitochondrial priming and sensitivity to killer T cells or ICIs. In mice, pharmacologically reducing the apoptotic threshold of ICI persisters prevented relapses. Thus, CNVs can drive the evolution of resistance to ICIs in melanoma, with tumor cell-intrinsic apoptotic threshold representing a target to curtail persister evolution.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"28 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145403933","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 : 2025-10-31DOI: 10.1016/j.immuni.2025.10.002
Hoyoung Lee, So-Young Kim, Sang-Hoon Kim, Seongju Jeong, Kyung Hwan Kim, Chang Gon Kim, June-Young Koh, Hyung-Don Kim, Ji Won Han, Hosun Yu, Wonyong Lee, Sunwoo Min, Su-Hyung Park, Hyuk Soo Eun, Eui-Cheol Shin
Human memory CD8+ T cells can undergo T cell receptor (TCR)-independent activation by interleukin-15 (IL-15) in a bystander manner. Bystander-activated CD8+ T cells contribute to host tissue injury through natural killer (NK)-like cytotoxicity during viral infections. However, detailed mechanisms underlying IL-15-induced bystander activation remain to be elucidated. In this study, we investigated the molecular regulation of bystander activation and NK-like cytotoxicity of human CCR7− memory CD8+ T cells. We found that TCR signals suppressed characteristic features of IL-15-induced CD8+ T cell activation. Ionomycin also suppressed IL-15-induced expression of NKG2D and NK cytotoxicity genes, indicating that Ca2+-calcineurin signaling suppressed bystander activation. Mechanistically, NFATc1 bound to AP-1, limiting its ability to induce expression of NK cytotoxicity-related genes. We also defined an IL-15-induced bystander activation gene set, which was validated in bystander CD8+ T cells from patients with hepatitis A virus infection. Our findings open avenues for investigating bystander CD8+ T cell activation and its regulation in pathological conditions.
{"title":"TCR signaling via NFATc1 constrains IL-15-induced bystander activation of human memory CD8+ T cells","authors":"Hoyoung Lee, So-Young Kim, Sang-Hoon Kim, Seongju Jeong, Kyung Hwan Kim, Chang Gon Kim, June-Young Koh, Hyung-Don Kim, Ji Won Han, Hosun Yu, Wonyong Lee, Sunwoo Min, Su-Hyung Park, Hyuk Soo Eun, Eui-Cheol Shin","doi":"10.1016/j.immuni.2025.10.002","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.10.002","url":null,"abstract":"Human memory CD8<sup>+</sup> T cells can undergo T cell receptor (TCR)-independent activation by interleukin-15 (IL-15) in a bystander manner. Bystander-activated CD8<sup>+</sup> T cells contribute to host tissue injury through natural killer (NK)-like cytotoxicity during viral infections. However, detailed mechanisms underlying IL-15-induced bystander activation remain to be elucidated. In this study, we investigated the molecular regulation of bystander activation and NK-like cytotoxicity of human CCR7<sup>−</sup> memory CD8<sup>+</sup> T cells. We found that TCR signals suppressed characteristic features of IL-15-induced CD8<sup>+</sup> T cell activation. Ionomycin also suppressed IL-15-induced expression of NKG2D and NK cytotoxicity genes, indicating that Ca<sup>2+</sup>-calcineurin signaling suppressed bystander activation. Mechanistically, NFATc1 bound to AP-1, limiting its ability to induce expression of NK cytotoxicity-related genes. We also defined an IL-15-induced bystander activation gene set, which was validated in bystander CD8<sup>+</sup> T cells from patients with hepatitis A virus infection. Our findings open avenues for investigating bystander CD8<sup>+</sup> T cell activation and its regulation in pathological conditions.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"114 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145403929","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 : 2025-10-31DOI: 10.1016/j.immuni.2025.10.013
Kevin Bi, Soki Kashima, Sabrina Y. Camp, Kevin Meli, Eddy Saad, Breanna M. Titchen, Chris Labaki, Ziad Bakouny, Erica M. Pimenta, Jihye Park, Erin Shannon, Jingxin Fu, Sherin Xirenayi, Jack Horst, Lotus Lum, Jeffrey J. Ishizuka, Toni K. Choueiri, David A. Braun, Eliezer M. Van Allen
Sustained type-I and type-II interferon (IFN) signaling can drive multiple mechanisms of resistance to immune checkpoint blockade (ICB). Here, we used single-cell RNA sequencing data to characterize the effects of IFNs in the tumor-immune microenvironment (TME) of renal cell carcinoma (RCC) and then examined how IFN-driven cellular phenotypes modulate ICB efficacy. Using mixed-effects models, we inferred the IFN inducibility of putative IFN-stimulated genes (ISGs) within cell types. Genes encoding inhibitory ligands and immune checkpoints were strongly expressed and IFN inducible in macrophages but less so in RCC tumor cells. In orthogonal clinical trial cohorts, a signature of myeloid IFNγ signaling, but not tumor IFNγ signaling, predicted primary resistance to first-line ICB plus anti-VEGF therapy. Functionally, IFNγ-conditioned macrophages inhibited T cell killing of RCC tumor cells in vitro. Our inferential modeling approach offers a framework for biomarker discovery through deconvolution of cytokine signaling effects in the TME and points to myeloid cells as mediators of tumor-extrinsic, IFN-driven resistance to immunotherapy in RCC.
{"title":"Myeloid cells mediate interferon-driven resistance to immunotherapy in advanced renal cell carcinoma","authors":"Kevin Bi, Soki Kashima, Sabrina Y. Camp, Kevin Meli, Eddy Saad, Breanna M. Titchen, Chris Labaki, Ziad Bakouny, Erica M. Pimenta, Jihye Park, Erin Shannon, Jingxin Fu, Sherin Xirenayi, Jack Horst, Lotus Lum, Jeffrey J. Ishizuka, Toni K. Choueiri, David A. Braun, Eliezer M. Van Allen","doi":"10.1016/j.immuni.2025.10.013","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.10.013","url":null,"abstract":"Sustained type-I and type-II interferon (IFN) signaling can drive multiple mechanisms of resistance to immune checkpoint blockade (ICB). Here, we used single-cell RNA sequencing data to characterize the effects of IFNs in the tumor-immune microenvironment (TME) of renal cell carcinoma (RCC) and then examined how IFN-driven cellular phenotypes modulate ICB efficacy. Using mixed-effects models, we inferred the IFN inducibility of putative IFN-stimulated genes (ISGs) within cell types. Genes encoding inhibitory ligands and immune checkpoints were strongly expressed and IFN inducible in macrophages but less so in RCC tumor cells. In orthogonal clinical trial cohorts, a signature of myeloid IFNγ signaling, but not tumor IFNγ signaling, predicted primary resistance to first-line ICB plus anti-VEGF therapy. Functionally, IFNγ-conditioned macrophages inhibited T cell killing of RCC tumor cells <em>in vitro</em>. Our inferential modeling approach offers a framework for biomarker discovery through deconvolution of cytokine signaling effects in the TME and points to myeloid cells as mediators of tumor-extrinsic, IFN-driven resistance to immunotherapy in RCC.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"15 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145403932","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 : 2025-10-30DOI: 10.1016/j.immuni.2025.10.005
Joseph Léger, Eva Artano, Delphine Coulais, Naomie Belletoise, Raoudha Fadhloun, Devin Kenney, Avinash Bhandoola, Christelle Harly
Understanding the mechanisms that initiate innate lymphoid cell (ILC) specification may reveal how ILC functions in immunity and tissue homeostasis are programmed. Using an Il7r-lineage tracing mouse strain, we identified developmental intermediates between lymphoid progenitors and Tcf7+ ILC progenitors in the mouse bone marrow (BM). Transcriptional analysis of these intermediates identified very early expression of the transcription factor nuclear factor, interleukin 3 regulated (NFIL3). Nfil3−/− mice lacked all BM ILC-specified precursors. Forced expression of NFIL3 in lymphoid progenitors induced Tcf7+ ILC-lineage cells capable of generating all ILC subsets and conventional natural killer cells. Transient activity of NFIL3 in lymphoid precursors recapitulated BM ILC development in vitro, leading to the generation of all adult ILCs. Mechanistically, NFIL3 initiated ILC specification by inducing expression of key transcriptional regulators of ILC development—Tox, Id2, Gata3, Tcf7, and Zbtb16. Our findings indicate an apex role for NFIL3 in ILC specification and provide an in vitro approach to generate ILC-lineage cells with potential therapeutic utility.
{"title":"The transcription factor NFIL3 drives innate lymphoid cell specification from lymphoid progenitors","authors":"Joseph Léger, Eva Artano, Delphine Coulais, Naomie Belletoise, Raoudha Fadhloun, Devin Kenney, Avinash Bhandoola, Christelle Harly","doi":"10.1016/j.immuni.2025.10.005","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.10.005","url":null,"abstract":"Understanding the mechanisms that initiate innate lymphoid cell (ILC) specification may reveal how ILC functions in immunity and tissue homeostasis are programmed. Using an <em>Il7r</em>-lineage tracing mouse strain, we identified developmental intermediates between lymphoid progenitors and <em>Tcf7</em><sup><em>+</em></sup> ILC progenitors in the mouse bone marrow (BM). Transcriptional analysis of these intermediates identified very early expression of the transcription factor nuclear factor, interleukin 3 regulated (NFIL3). <em>Nfil3</em><sup>−/−</sup> mice lacked all BM ILC-specified precursors. Forced expression of NFIL3 in lymphoid progenitors induced <em>Tcf7</em><sup><em>+</em></sup> ILC-lineage cells capable of generating all ILC subsets and conventional natural killer cells. Transient activity of NFIL3 in lymphoid precursors recapitulated BM ILC development <em>in vitro</em>, leading to the generation of all adult ILCs. Mechanistically, NFIL3 initiated ILC specification by inducing expression of key transcriptional regulators of ILC development—<em>Tox</em>, <em>Id2</em>, <em>Gata3</em>, <em>Tcf7</em>, and <em>Zbtb16</em>. Our findings indicate an apex role for NFIL3 in ILC specification and provide an <em>in vitro</em> approach to generate ILC-lineage cells with potential therapeutic utility.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"46 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145397591","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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