{"title":"DCs at the center of help: Origins and evolution of the three-cell-type hypothesis.","authors":"Renee Wu, Kenneth M Murphy","doi":"10.1084/jem.20211519","DOIUrl":"10.1084/jem.20211519","url":null,"abstract":"<p><p>Last year was the 10th anniversary of Ralph Steinman's Nobel Prize awarded for his discovery of dendritic cells (DCs), while next year brings the 50th anniversary of that discovery. Current models of anti-viral and anti-tumor immunity rest solidly on Steinman's discovery of DCs, but also rely on two seemingly unrelated phenomena, also reported in the mid-1970s: the discoveries of \"help\" for cytolytic T cell responses by Cantor and Boyse in 1974 and \"cross-priming\" by Bevan in 1976. Decades of subsequent work, controversy, and conceptual changes have gradually merged these three discoveries into current models of cell-mediated immunity against viruses and tumors.</p>","PeriodicalId":23015,"journal":{"name":"The Tokushima journal of experimental medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9098650/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85296020","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yong Du, Marie Dominique Ah Kioon, Paoline Laurent, Vidyanath Chaudhary, Michael Pierides, Chao Yang, David Oliver, Lionel B Ivashkiv, Franck J Barrat
{"title":"Chemokines form nanoparticles with DNA and can superinduce TLR-driven immune inflammation.","authors":"Yong Du, Marie Dominique Ah Kioon, Paoline Laurent, Vidyanath Chaudhary, Michael Pierides, Chao Yang, David Oliver, Lionel B Ivashkiv, Franck J Barrat","doi":"10.1084/jem.20212142","DOIUrl":"10.1084/jem.20212142","url":null,"abstract":"<p><p>Chemokines control the migratory patterns and positioning of immune cells to organize immune responses to pathogens. However, many chemokines have been associated with systemic autoimmune diseases that have chronic IFN signatures. We report that a series of chemokines, including CXCL4, CXCL10, CXCL12, and CCL5, can superinduce type I IFN (IFN-I) by TLR9-activated plasmacytoid DCs (pDCs), independently of their respective known chemokine receptors. Mechanistically, we show that chemokines such as CXCL4 mediate transcriptional and epigenetic changes in pDCs, mostly targeted to the IFN-I pathways. We describe that chemokines physically interact with DNA to form nanoparticles that promote clathrin-mediated cellular uptake and delivery of DNA in the early endosomes of pDCs. Using two separate mouse models of skin inflammation, we observed the presence of CXCL4 associated with DNA in vivo. These data reveal a noncanonical role for chemokines to serve as nucleic acid delivery vectors to modulate TLR signaling, with implications for the chronic presence of IFN-I by pDCs in autoimmune diseases.</p>","PeriodicalId":23015,"journal":{"name":"The Tokushima journal of experimental medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9161158/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88788085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cyril Planchais, Ignacio Fernández, Timothée Bruel, Guilherme Dias de Melo, Matthieu Prot, Maxime Beretta, Pablo Guardado-Calvo, Jérémy Dufloo, Luis M Molinos-Albert, Marija Backovic, Jeanne Chiaravalli, Emilie Giraud, Benjamin Vesin, Laurine Conquet, Ludivine Grzelak, Delphine Planas, Isabelle Staropoli, Florence Guivel-Benhassine, Thierry Hieu, Mikaël Boullé, Minerva Cervantes-Gonzalez, Marie-Noëlle Ungeheuer, Pierre Charneau, Sylvie van der Werf, Fabrice Agou, Jordan D Dimitrov, Etienne Simon-Lorière, Hervé Bourhy, Xavier Montagutelli, Félix A Rey, Olivier Schwartz, Hugo Mouquet
{"title":"Potent human broadly SARS-CoV-2-neutralizing IgA and IgG antibodies effective against Omicron BA.1 and BA.2.","authors":"Cyril Planchais, Ignacio Fernández, Timothée Bruel, Guilherme Dias de Melo, Matthieu Prot, Maxime Beretta, Pablo Guardado-Calvo, Jérémy Dufloo, Luis M Molinos-Albert, Marija Backovic, Jeanne Chiaravalli, Emilie Giraud, Benjamin Vesin, Laurine Conquet, Ludivine Grzelak, Delphine Planas, Isabelle Staropoli, Florence Guivel-Benhassine, Thierry Hieu, Mikaël Boullé, Minerva Cervantes-Gonzalez, Marie-Noëlle Ungeheuer, Pierre Charneau, Sylvie van der Werf, Fabrice Agou, Jordan D Dimitrov, Etienne Simon-Lorière, Hervé Bourhy, Xavier Montagutelli, Félix A Rey, Olivier Schwartz, Hugo Mouquet","doi":"10.1084/jem.20220638","DOIUrl":"10.1084/jem.20220638","url":null,"abstract":"<p><p>Memory B-cell and antibody responses to the SARS-CoV-2 spike protein contribute to long-term immune protection against severe COVID-19, which can also be prevented by antibody-based interventions. Here, wide SARS-CoV-2 immunoprofiling in Wuhan COVID-19 convalescents combining serological, cellular, and monoclonal antibody explorations revealed humoral immunity coordination. Detailed characterization of a hundred SARS-CoV-2 spike memory B-cell monoclonal antibodies uncovered diversity in their repertoire and antiviral functions. The latter were influenced by the targeted spike region with strong Fc-dependent effectors to the S2 subunit and potent neutralizers to the receptor-binding domain. Amongst those, Cv2.1169 and Cv2.3194 antibodies cross-neutralized SARS-CoV-2 variants of concern, including Omicron BA.1 and BA.2. Cv2.1169, isolated from a mucosa-derived IgA memory B cell demonstrated potency boost as IgA dimers and therapeutic efficacy as IgG antibodies in animal models. Structural data provided mechanistic clues to Cv2.1169 potency and breadth. Thus, potent broadly neutralizing IgA antibodies elicited in mucosal tissues can stem SARS-CoV-2 infection, and Cv2.1169 and Cv2.3194 are prime candidates for COVID-19 prevention and treatment.</p>","PeriodicalId":23015,"journal":{"name":"The Tokushima journal of experimental medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9206116/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82857222","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yifan Zhou, Yusra B Medik, B. Patel, D. Zamler, Sijie Chen, T. Chapman, Sarah Schneider, Rachel L. Babcock, Taylor T. Chrisikos, Laura M. Kahn, Allison M. Dyevoich, E. Park, Alexandria P. Cogdill, Daniel H Johnson, Sarah B. Johnson, K. Wani, D. Ledesma, C. Hudgens, Jingjing Wang, M. A. W. Khan, Aron Y Joon, W. Peng, Haiyan S. Li, R. Arora, Ximing Tang, M. G. Raso, Xuegong Zhang, W. Foo, M. Tetzlaff, G. Diehl, K. Clise-Dwyer, Elizabeth M Whitley, M. Gubin, J. Allison, P. Hwu, N. Ajami, A. Diab, J. Wargo, S. Watowich
{"title":"Intestinal toxicity to CTLA-4 blockade driven by IL-6 and myeloid infiltration","authors":"Yifan Zhou, Yusra B Medik, B. Patel, D. Zamler, Sijie Chen, T. Chapman, Sarah Schneider, Rachel L. Babcock, Taylor T. Chrisikos, Laura M. Kahn, Allison M. Dyevoich, E. Park, Alexandria P. Cogdill, Daniel H Johnson, Sarah B. Johnson, K. Wani, D. Ledesma, C. Hudgens, Jingjing Wang, M. A. W. Khan, Aron Y Joon, W. Peng, Haiyan S. Li, R. Arora, Ximing Tang, M. G. Raso, Xuegong Zhang, W. Foo, M. Tetzlaff, G. Diehl, K. Clise-Dwyer, Elizabeth M Whitley, M. Gubin, J. Allison, P. Hwu, N. Ajami, A. Diab, J. Wargo, S. Watowich","doi":"10.1158/1538-7445.am2022-5545","DOIUrl":"https://doi.org/10.1158/1538-7445.am2022-5545","url":null,"abstract":"Zhou et al. establish murine models of anti-CTLA-4–mediated intestinal irAEs. These reveal common immune signatures and the importance of fecal microbiome dysbiosis as irAE-driving mechanisms, which enable preclinical therapeutic interventions. Key immune features are validated in a cohort of melanoma patients with ICB-associated intestinal irAEs.","PeriodicalId":23015,"journal":{"name":"The Tokushima journal of experimental medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86249096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yang Zhang, Y. Ye, Xiaoqiang Tang, Hui Wang, Toshiko Tanaka, R. Tian, Xufei Yang, Lun Wang, Ying Xiao, Xiaomin Hu, Ye Jin, H. Pang, Tian Du, Honghong Liu, Lihong Sun, Shuo Xiao, R. Dong, L. Ferrucci, Z. Tian, Shuyang Zhang
{"title":"CCL17 acts as a novel therapeutic target in pathological cardiac hypertrophy and heart failure","authors":"Yang Zhang, Y. Ye, Xiaoqiang Tang, Hui Wang, Toshiko Tanaka, R. Tian, Xufei Yang, Lun Wang, Ying Xiao, Xiaomin Hu, Ye Jin, H. Pang, Tian Du, Honghong Liu, Lihong Sun, Shuo Xiao, R. Dong, L. Ferrucci, Z. Tian, Shuyang Zhang","doi":"10.1084/jem.20200418","DOIUrl":"https://doi.org/10.1084/jem.20200418","url":null,"abstract":"Zhang et al. identified chemokine CCL17 as a contributor to age-related heart failure in humans and mice via regulating plasticity and differentiation of T cells. Their findings suggested CCL17 as a novel therapeutic target in age-related heart failure.","PeriodicalId":23015,"journal":{"name":"The Tokushima journal of experimental medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83179540","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Xing Chen, Junjie Zhao, Tomasz Herjan, Lingzi Hong, Yun Liao, Caini Liu, Kommireddy Vasu, Han Wang, Austin Thompson, Paul L Fox, Brian R Gastman, Xiao Li, Xiaoxia Li
{"title":"IL-17-induced HIF1α drives resistance to anti-PD-L1 via fibroblast-mediated immune exclusion.","authors":"Xing Chen, Junjie Zhao, Tomasz Herjan, Lingzi Hong, Yun Liao, Caini Liu, Kommireddy Vasu, Han Wang, Austin Thompson, Paul L Fox, Brian R Gastman, Xiao Li, Xiaoxia Li","doi":"10.1084/jem.20210693","DOIUrl":"10.1084/jem.20210693","url":null,"abstract":"<p><p>Increasing evidence suggests that intratumoral inflammation has an outsized influence on antitumor immunity. Here, we report that IL-17, a proinflammatory cytokine widely associated with poor prognosis in solid tumors, drives the therapeutic failure of anti-PD-L1. By timing the deletion of IL-17 signaling specifically in cancer-associated fibroblasts (CAFs) in late-stage tumors, we show that IL-17 signaling drives immune exclusion by activating a collagen deposition program in murine models of cutaneous squamous cell carcinoma (cSCC). Ablation of IL-17 signaling in CAFs increased the infiltration of cytotoxic T cells into the tumor mass and sensitized otherwise resistant cSCC to anti-PD-L1 treatment. Mechanistically, the collagen deposition program in CAFs was driven by IL-17-induced translation of HIF1α, which was mediated by direct binding of Act1, the adaptor protein of IL-17 receptor, to a stem-loop structure in the 3' untranslated region (UTR) in Hif1α mRNA. Disruption of Act1's binding to Hif1α mRNA abolished IL-17-induced collagen deposition and enhanced anti-PD-L1-mediated tumor regression.</p>","PeriodicalId":23015,"journal":{"name":"The Tokushima journal of experimental medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8996325/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90704341","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jad N Kanbar, Shengyun Ma, Eleanor S Kim, Nadia S Kurd, Matthew S Tsai, Tiffani Tysl, Christella E Widjaja, Abigail E Limary, Brian Yee, Zhaoren He, Yajing Hao, Xiang-Dong Fu, Gene W Yeo, Wendy J Huang, John T Chang
{"title":"The long noncoding RNA Malat1 regulates CD8+ T cell differentiation by mediating epigenetic repression.","authors":"Jad N Kanbar, Shengyun Ma, Eleanor S Kim, Nadia S Kurd, Matthew S Tsai, Tiffani Tysl, Christella E Widjaja, Abigail E Limary, Brian Yee, Zhaoren He, Yajing Hao, Xiang-Dong Fu, Gene W Yeo, Wendy J Huang, John T Chang","doi":"10.1084/jem.20211756","DOIUrl":"10.1084/jem.20211756","url":null,"abstract":"<p><p>During an immune response to microbial infection, CD8+ T cells give rise to short-lived effector cells and memory cells that provide sustained protection. Although the transcriptional programs regulating CD8+ T cell differentiation have been extensively characterized, the role of long noncoding RNAs (lncRNAs) in this process remains poorly understood. Using a functional genetic knockdown screen, we identified the lncRNA Malat1 as a regulator of terminal effector cells and the terminal effector memory (t-TEM) circulating memory subset. Evaluation of chromatin-enriched lncRNAs revealed that Malat1 grouped with trans lncRNAs that exhibit increased RNA interactions at gene promoters and gene bodies. Moreover, we observed that Malat1 was associated with increased H3K27me3 deposition at a number of memory cell-associated genes through a direct interaction with Ezh2, thereby promoting terminal effector and t-TEM cell differentiation. Our findings suggest an important functional role of Malat1 in regulating CD8+ T cell differentiation and broaden the knowledge base of lncRNAs in CD8+ T cell biology.</p>","PeriodicalId":23015,"journal":{"name":"The Tokushima journal of experimental medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9127983/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74711280","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Zhi Li, Zewen K Tuong, Isaac Dean, Claire Willis, Fabrina Gaspal, Rémi Fiancette, Suaad Idris, Bethany Kennedy, John R Ferdinand, Ana Peñalver, Mia Cabantous, Syed Murtuza Baker, Jeremy W Fry, Gianluca Carlesso, Scott A Hammond, Simon J Dovedi, Matthew R Hepworth, Menna R Clatworthy, David R Withers
{"title":"In vivo labeling reveals continuous trafficking of TCF-1+ T cells between tumor and lymphoid tissue.","authors":"Zhi Li, Zewen K Tuong, Isaac Dean, Claire Willis, Fabrina Gaspal, Rémi Fiancette, Suaad Idris, Bethany Kennedy, John R Ferdinand, Ana Peñalver, Mia Cabantous, Syed Murtuza Baker, Jeremy W Fry, Gianluca Carlesso, Scott A Hammond, Simon J Dovedi, Matthew R Hepworth, Menna R Clatworthy, David R Withers","doi":"10.1084/jem.20210749","DOIUrl":"10.1084/jem.20210749","url":null,"abstract":"<p><p>Improving the efficacy of immune checkpoint therapies will require a better understanding of how immune cells are recruited and sustained in tumors. Here, we used the photoconversion of the tumor immune cell compartment to identify newly entering lymphocytes, determine how they change over time, and investigate their egress from the tumor. Combining single-cell transcriptomics and flow cytometry, we found that while a diverse mix of CD8 T cell subsets enter the tumor, all CD8 T cells retained within this environment for more than 72 h developed an exhausted phenotype, revealing the rapid establishment of this program. Rather than forming tumor-resident populations, non-effector subsets, which express TCF-1 and include memory and stem-like cells, were continuously recruited into the tumor, but this recruitment was balanced by concurrent egress to the tumor-draining lymph node. Thus, the TCF-1+ CD8 T cell niche in tumors is highly dynamic, with the circulation of cells between the tumor and peripheral lymphoid tissue to bridge systemic and intratumoral responses.</p>","PeriodicalId":23015,"journal":{"name":"The Tokushima journal of experimental medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9048291/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83641626","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jan C Lumibao, Jacob R Tremblay, Jasper Hsu, Dannielle D Engle
{"title":"Altered glycosylation in pancreatic cancer and beyond.","authors":"Jan C Lumibao, Jacob R Tremblay, Jasper Hsu, Dannielle D Engle","doi":"10.1084/jem.20211505","DOIUrl":"10.1084/jem.20211505","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDA) is one of the deadliest cancers and is projected to soon be the second leading cause of cancer death. Median survival of PDA patients is 6-10 mo, with the majority of diagnoses occurring at later, metastatic stages that are refractory to treatment and accompanied by worsening prognoses. Glycosylation is one of the most common types of post-translational modifications. The complex landscape of glycosylation produces an extensive repertoire of glycan moieties, glycoproteins, and glycolipids, thus adding a dynamic and tunable level of intra- and intercellular signaling regulation. Aberrant glycosylation is a feature of cancer progression and influences a broad range of signaling pathways to promote disease onset and progression. However, despite being so common, the functional consequences of altered glycosylation and their potential as therapeutic targets remain poorly understood and vastly understudied in the context of PDA. In this review, the functionality of glycans as they contribute to hallmarks of PDA are highlighted as active regulators of disease onset, tumor progression, metastatic capability, therapeutic resistance, and remodeling of the tumor immune microenvironment. A deeper understanding of the functional consequences of altered glycosylation will facilitate future hypothesis-driven studies and identify novel therapeutic strategies in PDA.</p>","PeriodicalId":23015,"journal":{"name":"The Tokushima journal of experimental medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9086500/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86207784","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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