Pub Date : 2024-10-25DOI: 10.1126/sciimmunol.ado0090
Francesca Cossarini, Joan Shang, Azra Krek, Zainab Al-Taie, Ruixue Hou, Pablo Canales-Herrerias, Minami Tokuyama, Michael Tankelevich, Adam Tillowitz, Divya Jha, Alexandra E. Livanos, Louise Leyre, Mathieu Uzzan, Gustavo Martinez-Delgado, Matthew D. Taylor, Keshav Sharma, Arno R. Bourgonje, Michael Cruz, Giorgio Ioannou, Travis Dawson, Darwin D''Souza, Seunghee Kim-Schulze, Ahmed Akm, Judith A. Aberg, Benjamin K. Chen, Douglas S. Kwon, Sacha Gnjatic, Alexandros D. Polydorides, Andrea Cerutti, Carmen Argmann, Ivan Vujkovic-Cvijin, Mayte Suarez-Fariñas, Francesca Petralia, Jeremiah J. Faith, Saurabh Mehandru
Gastrointestinal (GI) B cells and plasma cells (PCs) are critical to mucosal homeostasis and the host response to HIV-1 infection. Here, high-resolution mapping of human B cells and PCs sampled from the colon and ileum during both viremic and suppressed HIV-1 infection identified a reduction in germinal center (GC) B cells and follicular dendritic cells (FDCs) during HIV-1 viremia. Immunoglobulin A–positive (IgA+) PCs are the major cellular output of intestinal GCs and were significantly reduced during viremic HIV-1 infection. PC-associated transcriptional perturbations, including type I interferon signaling, persisted in antiretroviral therapy (ART)–treated individuals, suggesting ongoing disruption of the intestinal immune milieu during ART. GI humoral immune perturbations were associated with changes in the intestinal microbiome composition and systemic inflammation. These findings highlight a key immune defect in the GI mucosa due to HIV-1 viremia.
胃肠道（GI）B细胞和浆细胞（PC）对粘膜平衡和宿主对HIV-1感染的反应至关重要。在这里，我们对在HIV-1病毒感染和抑制感染期间从结肠和回肠取样的人类B细胞和浆细胞进行了高分辨率绘图，发现在HIV-1病毒血症期间，生殖中心（GC）B细胞和滤泡树突状细胞（FDCs）减少了。免疫球蛋白 A 阳性（IgA + ）PC 是肠道 GC 的主要细胞输出，在 HIV-1 病毒感染期间显著减少。在接受抗逆转录病毒疗法（ART）治疗的个体中，PC相关的转录扰动（包括I型干扰素信号转导）持续存在，这表明在抗逆转录病毒疗法期间肠道免疫环境持续受到破坏。肠道体液免疫扰动与肠道微生物组组成的变化和全身炎症有关。这些发现凸显了HIV-1病毒血症导致的消化道粘膜主要免疫缺陷。
{"title":"Gastrointestinal germinal center B cell depletion and reduction in IgA+ plasma cells in HIV-1 infection","authors":"Francesca Cossarini, Joan Shang, Azra Krek, Zainab Al-Taie, Ruixue Hou, Pablo Canales-Herrerias, Minami Tokuyama, Michael Tankelevich, Adam Tillowitz, Divya Jha, Alexandra E. Livanos, Louise Leyre, Mathieu Uzzan, Gustavo Martinez-Delgado, Matthew D. Taylor, Keshav Sharma, Arno R. Bourgonje, Michael Cruz, Giorgio Ioannou, Travis Dawson, Darwin D''Souza, Seunghee Kim-Schulze, Ahmed Akm, Judith A. Aberg, Benjamin K. Chen, Douglas S. Kwon, Sacha Gnjatic, Alexandros D. Polydorides, Andrea Cerutti, Carmen Argmann, Ivan Vujkovic-Cvijin, Mayte Suarez-Fariñas, Francesca Petralia, Jeremiah J. Faith, Saurabh Mehandru","doi":"10.1126/sciimmunol.ado0090","DOIUrl":"10.1126/sciimmunol.ado0090","url":null,"abstract":"<div >Gastrointestinal (GI) B cells and plasma cells (PCs) are critical to mucosal homeostasis and the host response to HIV-1 infection. Here, high-resolution mapping of human B cells and PCs sampled from the colon and ileum during both viremic and suppressed HIV-1 infection identified a reduction in germinal center (GC) B cells and follicular dendritic cells (FDCs) during HIV-1 viremia. Immunoglobulin A–positive (IgA<sup>+</sup>) PCs are the major cellular output of intestinal GCs and were significantly reduced during viremic HIV-1 infection. PC-associated transcriptional perturbations, including type I interferon signaling, persisted in antiretroviral therapy (ART)–treated individuals, suggesting ongoing disruption of the intestinal immune milieu during ART. GI humoral immune perturbations were associated with changes in the intestinal microbiome composition and systemic inflammation. These findings highlight a key immune defect in the GI mucosa due to HIV-1 viremia.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 100","pages":""},"PeriodicalIF":17.6,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.ado0090","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489635","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 : 2024-10-18DOI: 10.1126/sciimmunol.adt4547
{"title":"Erratum for the Research Article “Initiator cell death event induced by SARS-CoV-2 in the human airway epithelium” by K. Liang et al.","authors":"","doi":"10.1126/sciimmunol.adt4547","DOIUrl":"10.1126/sciimmunol.adt4547","url":null,"abstract":"","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 100","pages":""},"PeriodicalIF":17.6,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142451400","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-18DOI: 10.1126/sciimmunol.adt4549
{"title":"Erratum for the Research Article “Circulating KLRG1+ long-lived effector memory T cells retain the flexibility to become tissue resident” by E. D. Lucas et al.","authors":"","doi":"10.1126/sciimmunol.adt4549","DOIUrl":"10.1126/sciimmunol.adt4549","url":null,"abstract":"","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 100","pages":""},"PeriodicalIF":17.6,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142451401","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-18DOI: 10.1126/sciimmunol.adn9879
Fangda Li, Zaofeng Yang, Thomas M. Savage, Rosa L. Vincent, Kenia de los Santos-Alexis, Alexander Ahn, Mathieu Rouanne, Dylan L. Mariuzza, Tal Danino, Nicholas Arpaia
Interferon-γ (IFN-γ) is a potent cytokine critical for response to immunotherapy, yet conventional methods to systemically deliver this cytokine have been hindered by severe dose-limiting toxicities. Here, we engineered a strain of probiotic bacteria that home to tumors and locally release IFN-γ. A single intratumoral injection of these IFN-γ–producing bacteria was sufficient to drive systemic tumor antigen–specific antitumor immunity, without observable toxicity. Although cancer cells use various resistance mechanisms to evade immune responses, bacteria-derived IFN-γ overcame primary resistance to programmed cell death 1 (PD-1) blockade via activation of cytotoxic Foxp3−CD4+ and CD8+ T cells. Moreover, by activating natural killer (NK) cells, bacteria-derived IFN-γ also overcame acquired resistance mechanisms to PD-1 blockade, specifically loss-of-function mutations in IFN-γ signaling and antigen presentation pathways. Collectively, these results demonstrate the promise of combining IFN-γ–producing bacteria with PD-1 blockade as a therapeutic strategy for overcoming immunotherapy-resistant, locally advanced, and metastatic disease.
{"title":"Programmable bacteria synergize with PD-1 blockade to overcome cancer cell–intrinsic immune resistance mechanisms","authors":"Fangda Li, Zaofeng Yang, Thomas M. Savage, Rosa L. Vincent, Kenia de los Santos-Alexis, Alexander Ahn, Mathieu Rouanne, Dylan L. Mariuzza, Tal Danino, Nicholas Arpaia","doi":"10.1126/sciimmunol.adn9879","DOIUrl":"10.1126/sciimmunol.adn9879","url":null,"abstract":"<div >Interferon-γ (IFN-γ) is a potent cytokine critical for response to immunotherapy, yet conventional methods to systemically deliver this cytokine have been hindered by severe dose-limiting toxicities. Here, we engineered a strain of probiotic bacteria that home to tumors and locally release IFN-γ. A single intratumoral injection of these IFN-γ–producing bacteria was sufficient to drive systemic tumor antigen–specific antitumor immunity, without observable toxicity. Although cancer cells use various resistance mechanisms to evade immune responses, bacteria-derived IFN-γ overcame primary resistance to programmed cell death 1 (PD-1) blockade via activation of cytotoxic Foxp3<sup>−</sup>CD4<sup>+</sup> and CD8<sup>+</sup> T cells. Moreover, by activating natural killer (NK) cells, bacteria-derived IFN-γ also overcame acquired resistance mechanisms to PD-1 blockade, specifically loss-of-function mutations in IFN-γ signaling and antigen presentation pathways. Collectively, these results demonstrate the promise of combining IFN-γ–producing bacteria with PD-1 blockade as a therapeutic strategy for overcoming immunotherapy-resistant, locally advanced, and metastatic disease.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 100","pages":""},"PeriodicalIF":17.6,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adn9879","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142449590","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 : 2024-10-18DOI: 10.1126/sciimmunol.adg6453
Sreya Bagchi, Robert Yuan, Han-Li Huang, Weiruo Zhang, David Kung-Chun Chiu, Hyungjoo Kim, Sophia L. Cha, Lorna Tolentino, Joshua Lowitz, Yilin Liu, Anna Moshnikova, Oleg Andreev, Sylvia Plevritis, Edgar G. Engleman
Multiple cancers, including colorectal cancer (CRC), are more frequent and often more aggressive in individuals with obesity. Here, we showed that macrophages accumulated within tumors of patients with obesity and CRC and in obese CRC mice and that they promoted accelerated tumor growth. These changes were initiated by oleic acid accumulation and subsequent tumor cell–derived acid production and were driven by macrophage signaling through the acid-sensing receptor GPR65. We found a similar role for GPR65 in hepatocellular carcinoma (HCC) in obese mice. Tumors in patients with obesity and CRC or HCC also exhibited increased GPR65 expression, suggesting that the mechanism revealed here may contribute to tumor growth in a range of obesity-associated cancers and represent a potential therapeutic target.
{"title":"The acid-sensing receptor GPR65 on tumor macrophages drives tumor growth in obesity","authors":"Sreya Bagchi, Robert Yuan, Han-Li Huang, Weiruo Zhang, David Kung-Chun Chiu, Hyungjoo Kim, Sophia L. Cha, Lorna Tolentino, Joshua Lowitz, Yilin Liu, Anna Moshnikova, Oleg Andreev, Sylvia Plevritis, Edgar G. Engleman","doi":"10.1126/sciimmunol.adg6453","DOIUrl":"10.1126/sciimmunol.adg6453","url":null,"abstract":"<div >Multiple cancers, including colorectal cancer (CRC), are more frequent and often more aggressive in individuals with obesity. Here, we showed that macrophages accumulated within tumors of patients with obesity and CRC and in obese CRC mice and that they promoted accelerated tumor growth. These changes were initiated by oleic acid accumulation and subsequent tumor cell–derived acid production and were driven by macrophage signaling through the acid-sensing receptor GPR65. We found a similar role for GPR65 in hepatocellular carcinoma (HCC) in obese mice. Tumors in patients with obesity and CRC or HCC also exhibited increased GPR65 expression, suggesting that the mechanism revealed here may contribute to tumor growth in a range of obesity-associated cancers and represent a potential therapeutic target.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 100","pages":""},"PeriodicalIF":17.6,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adg6453","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142449595","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 : 2024-10-18DOI: 10.1126/sciimmunol.adl2986
Haerin Jung, Do-Hyun Kim, Roberto Efraín Díaz, J. Michael White, Summer Rucknagel, Lauryn Mosby, Yilin Wang, Sanjana Reddy, Emma S. Winkler, Ahmed O. Hassan, Baoling Ying, Michael S. Diamond, Richard M. Locksley, James S. Fraser, Steven J. Van Dyken
Environmental exposures increase the risk for severe lung disease, but specific drivers of persistent epithelial injury and immune dysfunction remain unclear. Here, we identify a feedback circuit triggered by chitin, a common component of airborne particles, that affects lung health after epithelial injury. In mice, epithelial damage disrupts lung chitinase activity, leading to environmental chitin accumulation, impaired epithelial renewal, and group 2 innate lymphoid cell (ILC2) activation. ILC2s, in turn, restore homeostasis by inducing acidic mammalian chitinase (AMCase) in regenerating epithelial cells and promoting chitin degradation, epithelial differentiation, and inflammatory resolution. Mice lacking AMCase or ILC2s fail to clear chitin and exhibit increased mortality and impaired epithelial regeneration after injury. These effects are ameliorated by chitinase replacement therapy, demonstrating that chitin degradation is crucial for recovery after various forms of lung perturbation. Thus, the ILC2-chitinase response circuit may serve as a target for alleviating persistent postinjury lung epithelial and immune dysfunction.
{"title":"An ILC2-chitinase circuit restores lung homeostasis after epithelial injury","authors":"Haerin Jung, Do-Hyun Kim, Roberto Efraín Díaz, J. Michael White, Summer Rucknagel, Lauryn Mosby, Yilin Wang, Sanjana Reddy, Emma S. Winkler, Ahmed O. Hassan, Baoling Ying, Michael S. Diamond, Richard M. Locksley, James S. Fraser, Steven J. Van Dyken","doi":"10.1126/sciimmunol.adl2986","DOIUrl":"10.1126/sciimmunol.adl2986","url":null,"abstract":"<div >Environmental exposures increase the risk for severe lung disease, but specific drivers of persistent epithelial injury and immune dysfunction remain unclear. Here, we identify a feedback circuit triggered by chitin, a common component of airborne particles, that affects lung health after epithelial injury. In mice, epithelial damage disrupts lung chitinase activity, leading to environmental chitin accumulation, impaired epithelial renewal, and group 2 innate lymphoid cell (ILC2) activation. ILC2s, in turn, restore homeostasis by inducing acidic mammalian chitinase (AMCase) in regenerating epithelial cells and promoting chitin degradation, epithelial differentiation, and inflammatory resolution. Mice lacking AMCase or ILC2s fail to clear chitin and exhibit increased mortality and impaired epithelial regeneration after injury. These effects are ameliorated by chitinase replacement therapy, demonstrating that chitin degradation is crucial for recovery after various forms of lung perturbation. Thus, the ILC2-chitinase response circuit may serve as a target for alleviating persistent postinjury lung epithelial and immune dysfunction.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 100","pages":""},"PeriodicalIF":17.6,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142449594","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-11DOI: 10.1126/sciimmunol.adk7237
Bu-Nam Jeon, Sujeong Kim, Yunjae Kim, Hyunkyung Yu, Changho Park, Gihyeon Kim, Youngeun Ha, Gyeong-yeon Kim, Hyunuk Kim, Karolina A. Palucka, Charles Lee, Miyoung Cha, Hansoo Park
Immune checkpoint inhibitors have substantial advanced tumor treatment, but their limited benefits and strong responses in only a subset of patients remain challenging. In this study, we explored the immunomodulatory function of contactin-4 (CNTN4). CNTN4 was highly expressed in tumor tissues, and expression impaired the antitumor function of T cells. CNTN4 bound to amyloid precursor protein (APP) on T cells, which attenuated conjugation between cancer cells and T cells, and diminished T cell receptor signaling cascades. We developed an anti-CNTN4 antibody (GENA-104A16) and an anti-APP antibody (5A7) that blocked the binding between CNTN4 and APP. Administration of either GENA-104A16 or 5A7 promoted antitumor T cell responses in a syngeneic mouse model and increased tumor-infiltrating lymphocytes in vivo. Furthermore, elevated CNTN4 levels were associated with poor prognosis and negatively correlated with various cytotoxic immune-related markers. These results suggest that CNTN4-APP is an inhibitory checkpoint in T cells and represents a promising therapeutic strategy for cancer immunotherapy.
免疫检查点抑制剂在晚期肿瘤治疗中发挥了重要作用，但其疗效有限，且仅在一部分患者中产生强烈反应，这一点仍具有挑战性。在这项研究中，我们探讨了接触素-4（CNTN4）的免疫调节功能。CNTN4在肿瘤组织中高表达，其表达损害了T细胞的抗肿瘤功能。CNTN4与T细胞上的淀粉样前体蛋白（APP）结合，削弱了癌细胞与T细胞之间的结合，并减弱了T细胞受体信号级联。我们开发了一种抗 CNTN4 抗体（GENA-104A16）和一种抗 APP 抗体（5A7），它们能阻断 CNTN4 和 APP 之间的结合。给小鼠注射 GENA-104A16 或 5A7 可促进合成小鼠模型中的抗肿瘤 T 细胞反应，并增加体内的肿瘤浸润淋巴细胞。此外，CNTN4 水平升高与预后不良有关，并与各种细胞毒性免疫相关标志物呈负相关。这些结果表明 CNTN4-APP 是 T 细胞的抑制性检查点，是一种很有前景的癌症免疫疗法策略。
{"title":"Contactin-4 suppresses antitumor T cell responses by engaging amyloid precursor protein","authors":"Bu-Nam Jeon, Sujeong Kim, Yunjae Kim, Hyunkyung Yu, Changho Park, Gihyeon Kim, Youngeun Ha, Gyeong-yeon Kim, Hyunuk Kim, Karolina A. Palucka, Charles Lee, Miyoung Cha, Hansoo Park","doi":"10.1126/sciimmunol.adk7237","DOIUrl":"10.1126/sciimmunol.adk7237","url":null,"abstract":"<div >Immune checkpoint inhibitors have substantial advanced tumor treatment, but their limited benefits and strong responses in only a subset of patients remain challenging. In this study, we explored the immunomodulatory function of contactin-4 (CNTN4). CNTN4 was highly expressed in tumor tissues, and expression impaired the antitumor function of T cells. CNTN4 bound to amyloid precursor protein (APP) on T cells, which attenuated conjugation between cancer cells and T cells, and diminished T cell receptor signaling cascades. We developed an anti-CNTN4 antibody (GENA-104A16) and an anti-APP antibody (5A7) that blocked the binding between CNTN4 and APP. Administration of either GENA-104A16 or 5A7 promoted antitumor T cell responses in a syngeneic mouse model and increased tumor-infiltrating lymphocytes in vivo. Furthermore, elevated CNTN4 levels were associated with poor prognosis and negatively correlated with various cytotoxic immune-related markers. These results suggest that CNTN4-APP is an inhibitory checkpoint in T cells and represents a promising therapeutic strategy for cancer immunotherapy.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 100","pages":""},"PeriodicalIF":17.6,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142406787","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-11DOI: 10.1126/sciimmunol.adp5216
Daniel Malouli, Husam Taher, Mandana Mansouri, Ravi F. Iyer, Jason Reed, Courtney Papen, John B. Schell, Teresa Beechwood, Thomas Martinson, David Morrow, Colette M. Hughes, Roxanne M. Gilbride, Kurt Randall, Julia C. Ford, Karina Belica, Sohita Ojha, Jonah B. Sacha, Benjamin N. Bimber, Scott G. Hansen, Louis J. Picker, Klaus Früh
Rhesus cytomegalovirus (RhCMV) vectors elicit major histocompatibility complex (MHC)–E–restricted CD8+ T cells that stringently control simian immunodeficiency virus (SIV) in rhesus macaques. These responses require deletion of eight RhCMV chemokine-like open reading frames (ORFs) that are conserved in human cytomegalovirus (HCMV). To determine whether HCMV encodes additional, nonconserved inhibitors of unconventional T cell priming, we inserted 41 HCMV-specific ORFs into a chemokine-deficient strain (68-1 RhCMV). Monitoring of epitope recognition revealed that HCMV UL18 prevented unconventional T cell priming, resulting in MHC-Ia–targeted responses. UL18 is homologous to MHC-I but does not engage T cell receptors and, instead, binds with high affinity to inhibitory leukocyte immunoglobulin-like receptor–1 (LIR-1). UL18 lacking LIR-1 binding no longer interfered with MHC-E–restricted T cell stimulation by RhCMV-infected cells or the induction of unconventionally restricted T cells. Thus, LIR-1 binding needs to be deleted from UL18 of HCMV/HIV vaccines to allow for the induction of protective MHC-E–restricted T cells.
恒河猴巨细胞病毒（RhCMV）载体可诱导主要组织相容性复合体（MHC）-E 限制性 CD8+ T 细胞，从而严格控制恒河猴体内的猿免疫缺陷病毒（SIV）。这些反应需要删除 8 个 RhCMV 趋化因子样开放阅读框（ORF），而这些开放阅读框在人类巨细胞病毒（HCMV）中是保守的。为了确定 HCMV 是否编码了额外的、非保守的非常规 T 细胞引物抑制因子，我们在趋化因子缺陷株（68-1 RhCMV）中插入了 41 个 HCMV 特异性 ORF。对表位识别的监测显示，HCMV UL18 能阻止非常规 T 细胞的启动，从而产生 MHC-Ia 靶向反应。UL18 与 MHC-I 同源，但不与 T 细胞受体结合，而是与抑制性白细胞免疫球蛋白样受体-1（LIR-1）高亲和力结合。缺乏 LIR-1 结合的 UL18 不再干扰 RhCMV 感染细胞对 MHC-E 限制性 T 细胞的刺激，也不再干扰非传统限制性 T 细胞的诱导。因此，需要从 HCMV/HIV 疫苗的 UL18 中删除 LIR-1 结合，以诱导保护性 MHC-E 限制性 T 细胞。
{"title":"Human cytomegalovirus UL18 prevents priming of MHC-E– and MHC-II–restricted CD8+ T cells","authors":"Daniel Malouli, Husam Taher, Mandana Mansouri, Ravi F. Iyer, Jason Reed, Courtney Papen, John B. Schell, Teresa Beechwood, Thomas Martinson, David Morrow, Colette M. Hughes, Roxanne M. Gilbride, Kurt Randall, Julia C. Ford, Karina Belica, Sohita Ojha, Jonah B. Sacha, Benjamin N. Bimber, Scott G. Hansen, Louis J. Picker, Klaus Früh","doi":"10.1126/sciimmunol.adp5216","DOIUrl":"10.1126/sciimmunol.adp5216","url":null,"abstract":"<div >Rhesus cytomegalovirus (RhCMV) vectors elicit major histocompatibility complex (MHC)–E–restricted CD8<sup>+</sup> T cells that stringently control simian immunodeficiency virus (SIV) in rhesus macaques. These responses require deletion of eight RhCMV chemokine-like open reading frames (ORFs) that are conserved in human cytomegalovirus (HCMV). To determine whether HCMV encodes additional, nonconserved inhibitors of unconventional T cell priming, we inserted 41 HCMV-specific ORFs into a chemokine-deficient strain (68-1 RhCMV). Monitoring of epitope recognition revealed that HCMV UL18 prevented unconventional T cell priming, resulting in MHC-Ia–targeted responses. UL18 is homologous to MHC-I but does not engage T cell receptors and, instead, binds with high affinity to inhibitory leukocyte immunoglobulin-like receptor–1 (LIR-1). UL18 lacking LIR-1 binding no longer interfered with MHC-E–restricted T cell stimulation by RhCMV-infected cells or the induction of unconventionally restricted T cells. Thus, LIR-1 binding needs to be deleted from UL18 of HCMV/HIV vaccines to allow for the induction of protective MHC-E–restricted T cells.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 100","pages":""},"PeriodicalIF":17.6,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142406788","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-04DOI: 10.1126/sciimmunol.adt3806
Eli C. Olson, Stephanie C. Eisenbarth
Dendritic cells sense confinement in the environment to induce migration in the absence of typical inflammatory stimuli.
树突状细胞在没有典型炎症刺激的情况下，会感知环境中的局限性，从而诱导迁移。
{"title":"Dendritic cells in a pinch: Migration during homeostasis","authors":"Eli C. Olson, Stephanie C. Eisenbarth","doi":"10.1126/sciimmunol.adt3806","DOIUrl":"10.1126/sciimmunol.adt3806","url":null,"abstract":"<div >Dendritic cells sense confinement in the environment to induce migration in the absence of typical inflammatory stimuli.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 100","pages":""},"PeriodicalIF":17.6,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142375909","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}
The interferon (IFN) response is vital for the effectiveness of immune checkpoint inhibition (ICI) therapy. Our previous research showed that KRAS (Kirsten rat sarcoma viral) mutation impairs the IFN response in colorectal cancer (CRC), with an unclear mechanism. Here, we demonstrate that KRAS accelerates double-stranded RNA (dsRNA) degradation, impairing dsRNA sensing and IFN response by down-regulating DExD/H-box helicase 6 (DDX60). DDX60 was identified as a KRAS target here and could bind to dsRNAs to protect against RNA-induced silencing complex (RISC)–mediated degradation. Overexpressing DDX60 induced dsRNA accumulation, reactivated IFN signaling, and increased CRC sensitivity to ICI therapy. Mechanistically, KRAS engaged the AKT (also known as protein kinase B)–GSK3β (glycogen synthase kinase-3 beta) pathway to suppress STAT3 phosphorylation, thereby inhibiting STAT3-driven DDX60 transcription. Our findings reveal a role for KRAS in dsRNA homeostasis, suggesting potential strategies to convert “cold” tumors to “hot” and to overcome ICI resistance in CRC with KRAS mutations.
{"title":"Oncogenic KRAS drives immunosuppression of colorectal cancer by impairing DDX60-mediated dsRNA accumulation and viral mimicry","authors":"Yi Zhou, Yaxin Zhang, Mingzhou Li, Tian Ming, Chao Zhang, Chengmei Huang, Jiexi Li, Fengtian Li, Huali Li, Enen Zhao, Feng Shu, Lingtao Liu, Xingyan Pan, Yijun Gao, Lin Tian, Libing Song, Huilin Huang, Wenting Liao","doi":"10.1126/sciimmunol.ado8758","DOIUrl":"10.1126/sciimmunol.ado8758","url":null,"abstract":"<div >The interferon (IFN) response is vital for the effectiveness of immune checkpoint inhibition (ICI) therapy. Our previous research showed that KRAS (Kirsten rat sarcoma viral) mutation impairs the IFN response in colorectal cancer (CRC), with an unclear mechanism. Here, we demonstrate that KRAS accelerates double-stranded RNA (dsRNA) degradation, impairing dsRNA sensing and IFN response by down-regulating DExD/H-box helicase 6 (DDX60). DDX60 was identified as a KRAS target here and could bind to dsRNAs to protect against RNA-induced silencing complex (RISC)–mediated degradation. Overexpressing DDX60 induced dsRNA accumulation, reactivated IFN signaling, and increased CRC sensitivity to ICI therapy. Mechanistically, KRAS engaged the AKT (also known as protein kinase B)–GSK3β (glycogen synthase kinase-3 beta) pathway to suppress STAT3 phosphorylation, thereby inhibiting STAT3-driven DDX60 transcription. Our findings reveal a role for KRAS in dsRNA homeostasis, suggesting potential strategies to convert “cold” tumors to “hot” and to overcome ICI resistance in CRC with KRAS mutations.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 100","pages":""},"PeriodicalIF":17.6,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142374627","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}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号