Immunology
Abstract
Aspergillus fumigatus is the most common cause of invasive aspergillosis (IA), a devastating infection in immunocompromised patients. Plasmacytoid dendritic cells (pDCs) regulate host defense against IA by enhancing neutrophil antifungal properties in the lung. Here, we define the pDC activation trajectory during A. fumigatus infection and the molecular events that underlie the protective pDC - neutrophil crosstalk. Fungus-induced pDC activation begins after bone marrow egress and results in pDC-dependent regulation of lung type I and type III IFN levels. These pDC-derived products act on type I and type III IFN receptor-expressing neutrophils and control neutrophil fungicidal activity and reactive oxygen species production via STAT1 signaling in a cell-intrinsic manner. Mechanistically, neutrophil STAT1 signaling regulates the transcription and expression of Cybb, which encodes one of five NADPH oxidase subunits. Thus, pDCs regulate neutrophil-dependent immunity against inhaled molds by controlling the local expression of a subunit required for NADPH oxidase assembly and activity in the lung.
Authors
Yahui Guo, Mariano A. Aufiero, Kathleen A.M. Mills, Simon A. Grassmann, Hyunu Kim, Mergim Gjonbalaj, Paul Zumbo, Audrey Billips, Katrina B. Mar, Yao Yu, Laura Echeverri Tirado, Lena Heung, Amariliz Rivera, Doron Betel, Joseph C. Sun, Tobias M. Hohl
Abstract
BRD4 is an epigenetic reader protein that regulates oncogenes such as myc in cancer. However, its additional role in shaping immune responses via regulation of inflammatory and myeloid cell responses is not yet fully understood. This work further characterized the multifaceted role of BRD4 in anti-tumor immunity. NanoString gene expression analysis of EMT6 tumors treated with a BRD4 inhibitor identified a reduction in myeloid gene expression signatures. Additionally, BRD4 inhibition significantly reduced myeloid derived suppressor cells (MDSC) in the spleens and tumors of mice in multiple tumor models and also decreased the release of tumor-derived MDSC growth and chemotactic factors. Pharmacologic inhibition of BRD4 in MDSC induced apoptosis and modulated expression of apoptosis regulatory proteins. A BRD4-myeloid specific knockout model suggested that the dominant mechanism of MDSC reduction after BRD4 inhibition was primarily through a direct effect on MDSC. BRD4 inhibition enhanced anti-PD-L1 therapy in the EMT6, 4T1, and LLC tumor models, and the efficacy of the combination treatment was dependent on CD8+ T cells and on BRD4 expression in the myeloid compartment. These results identify BRD4 as a regulator of MDSC survival and provide evidence to further investigate BRD4 inhibitors in combination with immune based therapies.
Authors
Himanshu Savardekar, Andrew Stiff, Alvin Liu, Robert Wesolowski, Emily Schwarz, Ian C. Garbarine, Megan C. Duggan, Sara Zelinskas, Jianying Li, Gabriella Lapurga, Alexander Abreo, Lohith Savardekar, Ryan Parker, Julia Sabella, Mallory J. DiVincenzo, Brooke Benner, Steven H. Sun, Dionisia Quiroga, Luke Scarberry, Gang Xin, Anup Dey, Keiko Ozato, Lianbo Yu, Merve Hasanov, Debasish Sundi, Richard C. Wu, Kari L. Kendra, William E. Carson III
Abstract
Gasdermin (GSDM) family proteins mediate tumor pyroptosis and impact cancer progression, but other than that, their involvement in the tumor immune microenvironment remains largely unknown. Here, we show that activation of GSDMD in human tumor specimens mainly occurs in tumor-infiltrating leukocytes. Significantly, GSDMD deficiency or its inactivation in CD4+ T cells disabled CD8+ T cell–mediated antitumor immunity and caused tumor outgrowth in mice. Further study uncovered that, via inducing IL-2 production, GSDMD was required for CD4+ T cells to provide help to CD8+ T cell function. Mechanistically, GSDMD was cleaved by TCR stimulation–activated caspase-8 to form GSDMD-N pores, which enhanced Ca2+ influx for IL-2 induction. Moreover, GSDMD activation and function were conserved in human CD4+ T cells and associated with favorable prognosis and improved response to anti–PD-1 immunotherapy in colonic and pancreatic cancer. We believe this study identifies a new nonpyroptotic role of GSDMD in tumor immunity, proposing GSDMD as a potential target for cancer immunotherapy.
Authors
Yihan Yao, Lingling Wang, Weiqin Jiang, Ning Wang, Mengjie Li, Wenlong Lin, Ting Zhang, Wanqiang Sheng, Xiaojian Wang
Abstract
Type 1 diabetes is characterized by the autoimmune destruction of pancreatic β cells, resulting in permanent loss of glucose homeostasis. Islet transplantation is a promising potential cure that remains hindered by immune rejection. We previously showed that ST8Sia6 expression on tumors reduced immune surveillance and hypothesized that this sialyltransferase could protect β cells from autoimmune destruction. Here, we demonstrate that ectopic expression of ST8Sia6 in β cells of female nonobese diabetic mice (NOD βST) decreased the spontaneous incidence of diabetes by 90% and preserved β cell mass. NOD βST mice had comparable insulitis at 8 weeks of age that did not progress over time compared with littermate controls. β Cell–autoreactive B and T cells were present in NOD βST mice, indicating a peripheral rather than central mechanism of immune tolerance. The islets of NOD βST mice displayed a dampened type 1 immune response and reduced IL-12p35 expression in dendritic cells compared with those of littermate controls. The peripheral protection persisted even after removal of ST8Sia6 expression at 20 weeks of age, indicating that transient expression was sufficient for establishment of tolerance. These results demonstrate that ST8Sia6 protects β cells from immune-mediated attack and rejection, highlighting its therapeutic potential for autoimmune disorders.
Authors
Justin Choe, Paul Belmonte, Sydney Crotts, Thanh Nguyen, David Friedman, Alexi Zastrow, Matthew Rajcula, Brady Hammer, Claire Wilhelm, Michael J. Shapiro, Aleksey Matveyenko, Virginia Smith Shapiro
Abstract
Authors
Alyssa M. Duffy, Anshika Goenka, Maryam I. Azeem, Azmain Taz, Sayalee V. Potdar, Sara A. Scott, Ellen Marin, Jonathan L. Kaufman, Craig C. Hofmeister, Nisha S. Joseph, Vikas A. Gupta, Sagar Lonial, Ajay K. Nooka, Madhav V. Dhodapkar, Kavita M. Dhodapkar
Abstract
Background: Anti-TNF biologics are widely used to treat patients with immune-mediated inflammatory diseases. In mouse models, the complete absence of TNF impairs germinal center (GC) responses. Less is known about the impact of anti-TNF therapy on specific immune responses in humans. Widespread vaccination against SARS-CoV-2 offered an unprecedented opportunity to investigate the effects of biological therapies on responses to specific immunization. Previous work demonstrated that inflammatory bowel disease (IBD) patients treated with anti-TNF biologics exhibit decreased Spike-specific antibody responses compared to IBD patients treated with anti-IL-12/23 or healthy controls, even after four doses of mRNA vaccine. Methods: Here we analyzed humoral responses to SARS-CoV-2 immunization using single-cell RNA-Sequencing and flow cytometry of Spike-specific memory B cells (MBC), as well as avidity measurements of plasma antibodies from IBD patients treated with anti-TNF or anti-IL-12/23 or from healthy controls. Results: We observed decreased somatic hypermutation in the B cell receptors of Spike-specific MBCs and decreased antigen-specific MBC accumulation following SARS-CoV-2 mRNA vaccination in anti-TNF treated IBD patients, compared to IBD patients treated with anti-IL-12/23 or healthy controls. This decreased somatic hypermutation in Spike-specific MBCs in anti-TNF treated patients correlated with decreased and delayed antibody affinity maturation and reduced neutralization activity. Conclusion: These data provide in vivo evidence that anti-TNF, but not anti-IL-12/23, therapy impairs the quantity and quality of antigen-specific GC outputs in humans. Funding: Juan and Stefania Speck (donation) and by Canadian Institutes of Health Research (CIHR)/COVID-Immunity Task Force (CITF) grants VR-1 172711, VS1-175545, GA2-177716, GA1-177703 and CIHR FDN 143301 &143350.
Authors
Michelle W. Cheung, Samantha Xu, Janna R. Shapiro, Freda Qi, Melanie Delgado-Brand, Karen Colwill, Roya Dayam, Ying Liu, Jenny Choi, Joanne M. Stempak, James M. Rini, Vinod Chandran, Mark S. Silverberg, Anne-Claude Gingras, Tania H. Watts
Abstract
Acute ischemic organ diseases such as acute myocardial infarction and acute kidney injury often result in irreversible tissue damage and progress to chronic heart failure (CHF) and chronic kidney disease (CKD), respectively. However, the molecular mechanisms underlying the development of CHF and CKD remain incompletely understood. Here, we show that mice deficient in CD300a, an inhibitory immunoreceptor expressed on myeloid cells, showed enhanced efferocytosis by tissue-resident macrophages and decreased damage-associated molecular patterns and pathogenic SiglecFhi neutrophils, resulting in milder inflammation-associated tissue injury than wild-type mice after ischemia and reperfusion (IR). Notably, we uncovered that CD300a-deficiency on SiglecFlo neutrophils increased the signal transducer and activator of transcription 3-mediated production of pro-angiogenic and anti-fibrotic factors, resulting in milder adverse remodeling after IR. Our results demonstrated that CD300a plays an important role in the pathogenesis of ischemic tissue injury and adverse remodeling in the heart and kidney.
Authors
Nanako Nishiyama, Hitoshi Koizumi, Chigusa Nakahashi-Oda, Satoshi Fujiyama, Xuewei Ng, Hanbin Lee, Fumie Abe, Jinao Li, Yan Xu, Takehito Sugasawa, Kazuko Tajiri, Taketaro Sadahiro, Masaki Ieda, Keiji Tabuchi, Kazuko Shibuya, Akira Shibuya
Abstract
Group 3 innate lymphoid cells (ILC3s) have emerged as an important player in the pathogenesis of neutrophilic asthma. However, the regulatory mechanism supporting ILC3 responses in lung remains largely unclear. Here, we demonstrated that stem cell factor (SCF) expression is significantly increased and positively correlated with IL-17A and MPO expression in asthmatic patients. Notably, we identified ILC3 as a major IL-17A-producing responder to SCF in lung. In mice, SCF synergized with IL-1β/IL-23 to enhance pulmonary ILC3 activation and neutrophilic inflammation. Mechanistically, SCF promoted ILC3 proliferation and cytokine production. Transcriptomic analysis revealed that SCF treatment upregulated the genes related to proliferation and Th17 differentiation, associated with increased AKT and STAT3 signaling. In contrast, deficiency of SCF receptor, c-Kit, reduced ILC3 proliferation and IL-17A production, resulting in the amelioration of airway hyperreactivity (AHR) and neutrophilic inflammation in mouse neutrophilic asthma model. Furthermore, genetic deletion of SCF in fibroblasts revealed fibroblasts as the primary source of SCF for ILC3 activation in lung. Moreover, administration of imatinib, a c-Kit inhibitor, alleviated LPS, air pollution or ovalbumin/LPS-induced AHR and neutrophilic inflammation. Our findings elucidated a positive modulatory role of SCF/c-Kit signaling in ILC3 responses during neutrophilic inflammation, offering a potential therapeutic target for neutrophilic asthma.
Authors
Jheng-Syuan Shao, Alan C. Lai, Wei-Chang Huang, Ko-Chien Wu, Po-Yu Chi, Yao-Ming Chang, Ya-Jen Chang
Abstract
The germinal center (GC) dark zone (DZ) and light zone (LZ) represent distinct anatomical regions in lymphoid tissue where B-cell proliferation, immunoglobulin diversification, and selection are coordinated. Diffuse Large B-cell Lymphomas (DLBCL) with DZ-like gene expression profiles exhibit poor outcomes, though reasons are unclear and are not directly related to proliferation. Physiological DZs exhibit an exclusion of T-cells, prompting exploration for whether T-cell paucity contributes to DZ-like DLBCL. We used spatial transcriptomic approaches to achieve higher resolution of T-cell spatial heterogeneity in the GC and to derive potential pathways that underlie T-cell exclusion. We showed that T-cell exclusion from the DZ was linked to DNA damage response (DDR) and chromatin compaction molecular features characterizing the spatial DZ signature, and that these programs were independent of AID deaminase activity. As ATR is a key regulator of DDR, we tested its role in the T-cell inhibitory DZ transcriptional imprint. ATR inhibition reversed not only the DZ transcriptional signature but also DZ T-cell exclusion in DZ-like DLBCL in vitro microfluidic models and in in vivo samples of murine lymphoid tissue. These findings highlight that ATR activity underpins a physiological scenario of immune silencing. ATR inhibition may reverse the immune silent state and enhance T-cell based immunotherapy in aggressive lymphomas with GC DZ-like characteristics.
Authors
Valeria Cancila, Giorgio Bertolazzi, Allison S.Y. Chan, Giovanni Medico, Giulia Bastianello, Gaia Morello, Daniel Paysan, Clemence Lai, Liang Hong, Girija Shenoy, Patrick W. Jaynes, Giovanna Schiavoni, Fabrizio Mattei, Silvia Piconese, Maria V. Revuelta, Francesco Noto, Luca Businaro, Adele De Ninno, Ilenia Cammarata, Fabio Pagni, Saradha Venkatachalapathy, Sabina Sangaletti, Arianna Di Napoli, Giada Cicio, Davide Vacca, Silvia Lonardi, Luisa Lorenzi, Andrés J.M. Ferreri, Beatrice Belmonte, Min Liu, Manikandan Lakshmanan, Michelle S.N. Ong, Biyan Zhang, Tingyi See, Kong-Peng Lam, Gabriele Varano, Mario P. Colombo, Silvio Bicciato, Giorgio Inghirami, Leandro Cerchietti, Maurilio Ponzoni, Roberta Zappasodi, Evelyn Metzger, Joseph Beechem, Fabio Facchetti, Marco Foiani, Stefano Casola, Anand D. Jeyasekharan, Claudio Tripodo
Abstract
BACKGROUND. Predicting individual vaccine responses is a substantial public health challenge. We developed immunaut, an open-source, data-driven framework for systems vaccinologists to analyze and predict immunological outcomes across diverse vaccination settings, beyond traditional assessments. METHODS. Using a comprehensive live attenuated influenza vaccine (LAIV) dataset from 244 Gambian children, immunaut integrated pre- and post-vaccination humoral, mucosal, cellular, and transcriptomic data. Through advanced modeling, our framework provided a holistic, systems-level view of LAIV-induced immunity. RESULTS. The analysis identified three distinct immunophenotypic profiles driven by baseline immunity: (1) CD8 T-cell responders with strong pre-existing immunity boosting memory T-cell responses; (2) Mucosal responders with prior influenza A virus immunity developing robust mucosal IgA and subsequent influenza B virus seroconversion; and (3) Systemic, broad influenza A virus responders starting from immune naivety who mounted broad systemic antibody responses. Pathway analysis revealed how pre-existing immune landscapes and baseline features, such as mucosal preparedness and cellular support, quantitatively dictate vaccine outcomes. CONCLUSION. Our findings emphasize the power of integrative, predictive frameworks for advancing precision vaccinology. The immunaut framework is a valuable resource for deciphering vaccine response heterogeneity and can be applied to optimize immunization strategies across diverse populations and vaccine platforms. FUNDING. Wellcome Trust (110058/Z/15/Z); Bill & Melinda Gates Foundation (INV-004222); HIC-Vac consortium; NIAID (R21 AI151917); NIAID CEIRR Network (75N93021C00045).
Authors
Stephanie Hao, Ivan Tomic, Benjamin B. Lindsey, Ya Jankey Jagne, Katja Hoschler, Adam Meijer, Juan Manuel Carreño Quiroz, Philip Meade, Kaori Sano, Chikondi Peno, André G. Costa-Martins, Debby Bogaert, Beate Kampmann, Helder Nakaya, Florian Krammer, Thushan I. de Silva, Adriana Tomic
Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)