Aldo Ummarino, Alba Pensado-López, Roberta Migliore, Lourdes Alcaide-Ruggiero, Nicholas Calà, Michele Caputo, Francesco M. Gambaro, Clément Anfray, Flavio L. Ronzoni, Elizaveta Kon, Paola Allavena, Fernando Torres Andón
{"title":"An in vitro model for osteoarthritis using long-cultured inflammatory human macrophages repeatedly stimulated with TLR agonists","authors":"Aldo Ummarino, Alba Pensado-López, Roberta Migliore, Lourdes Alcaide-Ruggiero, Nicholas Calà, Michele Caputo, Francesco M. Gambaro, Clément Anfray, Flavio L. Ronzoni, Elizaveta Kon, Paola Allavena, Fernando Torres Andón","doi":"10.1002/eji.202350507","DOIUrl":"10.1002/eji.202350507","url":null,"abstract":"<p>Osteoarthritis (OA) is characterized by an abundance of inflammatory M1-like macrophages damaging local tissues. The search for new potential drugs for OA suffers from the lack of appropriate methods of long-lasting inflammation. Here we developed and characterized an <i>in vitro</i> protocol of long-lasting culture of primary human monocyte-derived macrophages differentiated with a combination of M-CSF+GM-CSF that optimally supported long-cultured macrophages (LC-Mϕs) for up to 15 days, unlike their single use. Macrophages repeatedly stimulated for 15 days with the TLR2 ligand Pam3CSK4 (LCS-Mϕs), showed sustained levels over time of IL-6, CCL2, and CXCL8, inflammatory mediators that were also detected in the synovial fluids of OA patients. Furthermore, macrophages isolated from the synovia of two OA patients showed an expression profile of inflammation-related genes similar to that of LCS-Mϕs, validating our protocol as a model of chronically activated inflammatory macrophages. Next, to confirm that these LCS-Mϕs could be modulated by anti-inflammatory compounds, we employed dexamethasone and/or celecoxib, two drugs widely used in OA treatment, that significantly inhibited the production of inflammatory mediators. This easy-to-use <i>in vitro</i> protocol of long-lasting inflammation with primary human macrophages could be useful for the screening of new compounds to improve the therapy of inflammatory disorders.</p>","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"53 12","pages":""},"PeriodicalIF":5.4,"publicationDate":"2023-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/eji.202350507","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10242827","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Activation and differentiation of cognate T cells by a dextran-based antigen-presenting system for cancer immunotherapy","authors":"Dhrubajyoti Mahata, Debangshu Mukherjee, Debarati Biswas, Shyam Basak, Aditya Jyoti Basak, Imlilong Jamir, Nidhi Pandey, Huma Khatoon, Dibyendu Samanta, Amit Basak, Gayatri Mukherjee","doi":"10.1002/eji.202350528","DOIUrl":"10.1002/eji.202350528","url":null,"abstract":"<p>Immunotherapeutic modulation of antigen-specific T-cell responses instead of the whole repertoire helps avoid immune-related adverse events. We have developed an artificial antigen-presenting system (aAPS) where multiple copies of a multimeric peptide-MHC class I complex presenting a murine class I MHC restricted ovalbumin-derived peptide (signal 1), along with a costimulatory ligand (signal 2) are chemically conjugated to a dextran backbone. Cognate naive CD8<sup>+</sup> T cells, when treated with this aAPS underwent significant expansion and showed an activated phenotype. Furthermore, elevated expression of effector cytokines led to the differentiation of these cells to cytotoxic T lymphocytes which resulted in target cell lysis, indicative of the functional efficacy of the aAPS. CD8<sup>+</sup> T cells with decreased proliferative potential due to repeated antigenic stimulation could also be re-expanded by the developed aAPS. Thus, the developed aAPS warrants further engineering for future application as a rapidly customizable personalized immunotherapeutic agent, incorporating patient-specific MHC-restricted tumor antigens and different costimulatory signals to modulate both naive and antigen-experienced but exhausted tumor-specific T cells in cancer.</p>","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"53 12","pages":""},"PeriodicalIF":5.4,"publicationDate":"2023-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10564920","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Joint Conference of the Société Française d'Immunologie (SFI) and the Deutsche Gesellschaft für Immunologie (DGfI), 26–29 September, 2023, Strasbourg, France","authors":"","doi":"10.1002/eji.202370300","DOIUrl":"https://doi.org/10.1002/eji.202370300","url":null,"abstract":"","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"53 S2","pages":""},"PeriodicalIF":5.4,"publicationDate":"2023-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/eji.202370300","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6574814","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sihan Wu, Xuan Zhang, Cuiping Hu, Yajie Zhong, Jun Chen, Wai Po Chong
{"title":"CD8+ T cells reduce neuroretina inflammation in mouse by regulating autoreactive Th1 and Th17 cells through IFN-γ","authors":"Sihan Wu, Xuan Zhang, Cuiping Hu, Yajie Zhong, Jun Chen, Wai Po Chong","doi":"10.1002/eji.202350574","DOIUrl":"10.1002/eji.202350574","url":null,"abstract":"<p>Various regulatory CD8<sup>+</sup> T-cell subsets have been proposed for immune tolerance and have been implicated in controlling autoimmune diseases. However, their phenotypic identities and suppression mechanisms are not yet understood. This study found that coculture of T-cell receptor (TCR)- or interferon (IFN)-β-activated CD8<sup>+</sup> T cells significantly suppressed the cytokine production of Th1 and Th17 cells. By experimenting with the experimental autoimmune uveitis (EAU), we found that adoptive transfer of TCR or IFN-β-activated CD8<sup>+</sup> T cells significantly lessened disease development in an IFN-γ-dependent manner with a decreased uveitogenic Th1 and Th17 response. Interestingly, after adoptive transfer into the EAU mice, the IFN-γ<sup>+</sup>CD8<sup>+</sup> T cells were recruited more efficiently into the secondary lymphoid organs during the disease-priming phase. This recruitment depends on the IFN-γ-inducible chemokine receptor CXCR3; knocking out CXCR3 abolishes the protective effect of CD8<sup>+</sup> T cells in EAU. In conclusion, we identified the critical role of IFN-γ for CD8<sup>+</sup> T cells to inhibit Th1 and Th17 responses and ameliorate EAU. CXCR3 is necessary to recruit IFN-γ<sup>+</sup>CD8<sup>+</sup> T cells to the secondary lymphoid organ for the regulation of autoreactive Th1 and Th17 cells.</p>","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"53 12","pages":""},"PeriodicalIF":5.4,"publicationDate":"2023-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/eji.202350574","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10284293","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Bram W. van Os, Winnie G. Vos, Laura A. Bosmans, Claudia M. van Tiel, Myrthe den Toom, Linda Beckers, Merel Admiraal, Marten A. Hoeksema, Menno P. de Winther, Esther Lutgens
{"title":"CD40L modulates CD4+ T-cell activation through receptor for activated C kinase 1","authors":"Bram W. van Os, Winnie G. Vos, Laura A. Bosmans, Claudia M. van Tiel, Myrthe den Toom, Linda Beckers, Merel Admiraal, Marten A. Hoeksema, Menno P. de Winther, Esther Lutgens","doi":"10.1002/eji.202350520","DOIUrl":"10.1002/eji.202350520","url":null,"abstract":"<p>Inhibition of the co-stimulatory ligand CD40L has shown beneficial effects in many experimental models of autoimmune disease and inflammation. Here, we show that CD40L deficiency in T cells in mice causes a reduction of CD4<sup>+</sup> T-cell activation and specifically a strong reduction in IFN-γ-producing Th1 cells. In vitro, we could not reproduce this antigen presenting cell-dependent effects, but found that T-cell CD40L affects cell death and proliferation. We identified receptor of activated C kinase, the canonical PKC binding partner and known to drive proliferation and apoptosis, as a mediator of CD40L reverse signaling. Furthermore, we found that CD40L clustering stabilizes IFN-γ mediated Th1 polarization through STAT1, a known binding partner of receptor of activated C kinase. Together this highlights the importance of both CD40L forward and reverse signaling.</p>","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"53 12","pages":""},"PeriodicalIF":5.4,"publicationDate":"2023-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10189894","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Cover Story: Eur. J. Immunol. 9'23","authors":"","doi":"10.1002/eji.202370091","DOIUrl":"https://doi.org/10.1002/eji.202370091","url":null,"abstract":"<p>Our cover illuminates fibroblasts and endothelial cells in a human tonsil by immunofluorescent staining. Smooth muscle actin identifies vascular smooth muscle cells (bright yellow) that encircle CD34<sup>+</sup> endothelial cells (green). Smooth muscle actin-expressing perivascular reticular cells (dim yellow) are also identified. The image is taken from Brandstadter et al., where the authors demonstrate an approach of whole-tissue cryopreservation that preserves a sensitive and rare cell population, nonhematopoietic lymph node stromal cells (LNSC), in human tonsils and lymph nodes. Such approach will enable biobanking and studies of LNSC in human diseases.\u0000\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"53 9","pages":""},"PeriodicalIF":5.4,"publicationDate":"2023-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/eji.202370091","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6303014","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Costimulatory capacity of CD137 mAbs on T cells depends on elaborate CRD structures but not on blocking ligand‒receptor binding","authors":"Xin Jin, Ling Yi, Xiaojue Wang, Zhuohong Yan, Panjian Wei, Bin Yang, Hongtao Zhang","doi":"10.1002/eji.202350493","DOIUrl":"10.1002/eji.202350493","url":null,"abstract":"<p>CD137 is mainly a costimulatory receptor of CD8+ T cells. Two representative CD137 antibodies, utomilumab, and urelumab, show different costimulatory capacities in clinical trials. Balancing the antitumor effect and systemic toxicity of T cells activated by CD137 signaling is a challenge that requires clinical consideration. In this study, a panel of specific anti-human CD137 monoclonal antibodies (mAbs) were prepared and their affinities, isotypes, CD137-CRD (cysteine-rich domain) binding regions, cross-reactivity to mouse and rhesus CD137, inhibition of ligand‒receptor binding and costimulatory activities were analyzed. The results showed that anti-human CD137 mAbs had high cross-reactivity with rhesus CD137. MAbs fell into three clusters according to their different binding regions of the CD137 extracellular domain. They bound to CRDI+CRDII, CRDIII or CRDIV+STP. CRDIII-binding mAbs had the strongest blocking activity. Highly costimulatory CD137 mAbs showed stronger abilities to promote CD8+ T-cell proliferation. However, the costimulatory capacity of mAbs on T cells was not closely related to their ability to block CD137L-CD137 binding and may be controlled by more elaborate CRD conformational structures. This study provides additional information for the development of next-generation CD137 mAbs to meet clinical needs.</p>","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"53 12","pages":""},"PeriodicalIF":5.4,"publicationDate":"2023-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10168016","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yongyi Feng, Chunliu Huang, Yingzhao Wang, Jun Chen
{"title":"SIRPα: A key player in innate immunity","authors":"Yongyi Feng, Chunliu Huang, Yingzhao Wang, Jun Chen","doi":"10.1002/eji.202350375","DOIUrl":"10.1002/eji.202350375","url":null,"abstract":"<p>Signal regulatory protein alpha (SIRPα) is a crucial inhibitory regulator expressed on the surface of myeloid cells, including macrophages, dendritic cells, monocytes, neutrophils, and microglia. SIRPα plays an indispensable role in innate immune and adoptive immune responses in cancer immunology, tissue homeostasis, and other physiological or phycological conditions. This review provides an overview of the research history, ligands, signal transduction pathways, and functional mechanisms associated with SIRPα. Additionally, we summarize the therapeutic implications of targeting SIRPα as a promising novel strategy in immuno-oncology.</p>","PeriodicalId":165,"journal":{"name":"European Journal of Immunology","volume":"53 11","pages":""},"PeriodicalIF":5.4,"publicationDate":"2023-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10631522","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}