Immunology
Abstract
A prophylactic hepatitis C virus (HCV) vaccine that elicits neutralizing antibodies could be key to HCV eradication. However, the genetic and antigenic properties of HCV envelope (E1E2) proteins capable of inducing anti-HCV broadly neutralizing antibodies (bNAbs) in humans have not been defined. Here, we investigated the development of bNAbs in longitudinal plasma of HCV-infected persons with persistent infection or spontaneous clearance of multiple reinfections. By measuring plasma antibody neutralization of a heterologous virus panel, we found that the breadth and potency of the antibody response increased upon exposure to multiple genetically distinct infections and with longer duration of viremia. Greater genetic divergence between infecting strains was not associated with enhanced neutralizing breadth. Rather, repeated exposure to antigenically-related, antibody sensitive E1E2s was associated with potent bNAb induction. These data reveal that a prime-boost vaccine strategy with genetically distinct, antibody sensitive viruses is a promising approach to induce potent bNAbs in humans.
Authors
Nicole Frumento, Alexis Figueroa, Tingchang Wang, Muhammad Nauman Zahid, Shuyi Wang, Guido Massaccesi, Georgia Stavrakis, James E. Crowe, Jr., Andrew I. Flyak, Hongkai Ji, Stuart C. Ray, George Shaw, Andrea L Cox, Justin R. Bailey
Abstract
In lymphopenic environments, secondary lymphoid organs regulate the size of B and T-cell compartments by supporting homeostatic proliferation of mature lymphocytes. The molecular mechanisms underlying these responses and their functional consequences remain incompletely understood. To evaluate homeostasis of the mature B-cell pool during lymphopenia, we turned to an adoptive transfer model of purified follicular B-cells into Rag2-/- mouse recipients. Highly purified follicular B-cells transdifferentiated into marginal zone-like B-cells when transferred into Rag2-/- lymphopenic hosts, but not into wild-type hosts. In lymphopenic spleens, transferred B-cells gradually lost their follicular phenotype and acquired characteristics of marginal zone B-cells, as judged by cell surface phenotype, expression of integrins and chemokine receptors, positioning close to the marginal sinus, and an ability to rapidly generate functional plasma cells. Initiation of follicular to marginal zone B-cell transdifferentiation preceded proliferation. Furthermore, the transdifferentiation process was dependent on Notch2 receptors in B-cells and expression of Delta-like1 Notch ligands by splenic Ccl19-Cre+ fibroblastic stromal cells. Gene expression analysis showed rapid induction of Notch-regulated transcripts followed by upregulated Myc expression and acquisition of broad transcriptional features of marginal zone B-cells. Thus, naïve mature B-cells are endowed with plastic transdifferentiation potential in response to increased stromal Notch ligand availability during lymphopenia.
Authors
Daniela Gómez Atria, Brian T. Gaudette, Jennifer Londregan, Samantha Kelly, Eric Perkey, Anneka Allman, Bhaskar Srivastava, Ute Koch, Freddy Radtke, Burkhard Ludewig, Christian W. Siebel, Russell J.H. Ryan, Tanner F. Robertson, Janis K. Burkhardt, Warren S. Pear, David Allman, Ivan Maillard
Abstract
Determinants of the acquisition and maintenance of maternal microchimerism (MMc) during infancy and the impact of MMc on infant immune responses are unknown. We examined factors which influence MMc detection and level across infancy and the effect of MMc on T cell responses to BCG vaccination in a cohort of HIV exposed, uninfected and HIV unexposed infants in South Africa. MMc was measured in whole blood from 58 infants using a panel of quantitative PCR assays at day one and 7, 15, and 36 weeks of life. Infants received BCG at birth, and selected whole blood samples from infancy were stimulated in vitro with BCG and assessed for polyfunctional CD4+ T cell responses. MMc was present in most infants across infancy with levels ranging from 0-1,193/100,000 genomic equivalents and was positively impacted by absence of maternal HIV, maternal-infant HLA compatibility, infant female sex, and exclusive breastfeeding. Initiation of maternal antiretroviral therapy prior to pregnancy partially restored MMc levels in HIV exposed, uninfected infants. Birth MMc was associated with an improved polyfunctional CD4+ T cell response to BCG. These data emphasize that both maternal and infant factors influence MMc, which may subsequently impact infant T cell responses.
Authors
Christina Balle, Blair Armistead, Agano Kiravu, Xiaochang Song, Anna-Ursula Happel, Angela A. Hoffmann, Sami B. Kanaan, J. Lee Nelson, Clive M. Gray, Heather B. Jaspan, Whitney E. Harrington
Abstract
BACKGROUND. Patients undergoing immune-modifying therapies demonstrate a reduced humoral response after COVID-19 vaccination, but we lack a proper evaluation of the impact of such therapies on vaccine-induced T cell responses. METHODS. We longitudinally characterized humoral and Spike-specific T cell responses in inflammatory bowel disease (IBD) patients who are on antimetabolite therapy (azathioprine or methotrexate), TNF inhibitors and/or other biologic treatment (anti-integrin or anti-p40) for up to 6 months after completing two-dose COVID-19 mRNA vaccination. RESULTS. We demonstrated that a Spike-specific T cell response is not only induced in treated IBD patients at levels similar to healthy individuals, but also sustained at higher magnitude for up to 6 months after vaccination, particularly in those treated with TNF inhibitor therapy. Furthermore, the Spike-specific T cell response in these patients is mainly preserved against mutations present in SARS-CoV-2 B.1.1.529 (Omicron) and characterized by a Th1/IL-10 cytokine profile. CONCLUSION. Despite the humoral response defects, patients under immune-modifying therapies demonstrated a favorable profile of vaccine-induced T cell responses that might still provide a layer of COVID-19 protection. FUNDING. This study was funded by the National Centre for Infectious Diseases NCID Catalyst Grant (FY2021ES) and the National Research Fund Competitive Research Programme (NRF-CRP25-2020-0003). The funders played no role in the design, conduct, or reporting of this study.
Authors
Martin Qui, Nina Le Bert, Webber Pak Wo Chan, Malcolm Tan, Shou Kit Hang, Smrithi Hariharaputran, Jean Xiang Ying Sim, Jenny Guek Hong Low, Weiling Ng, Wei Yee Wan, Tiing Leong Ang, Antonio Bertoletti, Ennaliza Salazar
IL-33 acts as a costimulatory signal to generate alloreactive Th1 cells in graft-versus-host disease
Abstract
Antigen-presenting cells (APC) integrate signals emanating from local pathology and program appropriate T cell responses. In allogeneic hematopoietic stem cell transplantation (alloHCT), recipient conditioning releases Damage-Associated Molecular Patterns (DAMPs) that generate pro-inflammatory APC that secrete IL-12, which is a driver of donor Type 1 T helper (Th1) responses causing graft vs. host disease (GVHD). Nevertheless, other mechanisms exist to initiate alloreactive T cells responses, as recipients with disrupted DAMP signaling or lacking IL-12 develop GVHD. We established that tissue damage signals are perceived directly by donor CD4+ T cells and promoted T cell expansion and differentiation. Specifically, the fibroblastic reticular cell-derived DAMP, IL-33, is increased by recipient conditioning and is critical for the initial activation, proliferation, and differentiation of alloreactive Th1 cells. IL-33-stimulation of CD4+ T cell was not required for lymphopenia-induced expansion, however. IL-33 promoted IL-12-independent expression of Tbet and generation of Th1 cells that infiltrated GVHD target tissues. Mechanistically, IL-33 augmented CD4+ T cell TCR-associated signaling pathways in response to alloantigen. This enhanced T cell expansion and Th1 polarization, but inhibited the expression of regulatory molecules like IL-10 and Foxp3. These data established an unappreciated role for IL-33 as a costimulatory signal for donor Th1 generation after alloHCT.
Authors
Gaelen K. Dwyer, Lisa R. Mathews, Jose A. Villegas, Anna Lucas, Anne Gonzalez de Peredo, Bruce R. Blazar, Jean-Philippe Girard, Amanda C. Poholek, Sanjiv A. Luther, Warren Shlomchik, Hēth R. Turnquist
Abstract
Chimeric antigen receptor (CAR) T-cell expansion and persistence represent key factors to achieve complete responses and prevent relapses. These features are typical of early memory T cells, which can be highly enriched through optimized manufacturing protocols. Here, we investigated the efficacy and safety profiles of CAR T-cell products generated from pre-selected naive/stem memory T cells (TN/SCM), as compared to unselected T cells (TBULK). Notwithstanding their reduced effector signature in vitro, limiting CAR TN/SCM doses showed superior antitumor activity and the unique ability to counteract leukemia re-challenge in hematopoietic stem/precursor cell-humanized mice, featuring increased expansion rates and persistence, together with an ameliorated exhaustion and memory phenotype. Most relevantly, CAR TN/SCM proved to be intrinsically less prone to induce severe cytokine release syndrome, independently of the costimulatory endodomain employed. This safer profile was associated with milder T-cell activation, which translated in reduced monocyte activation and cytokine release. These data suggest that CAR TN/SCM are endowed with a wider therapeutic index compared to CAR TBULK.
Authors
Silvia Arcangeli, Camilla Bove, Claudia Mezzanotte, Barbara Camisa, Laura Falcone, Francesco Manfredi, Eugenia Bezzecchi, Rita El Khoury, Rossana Norata, Francesca Sanvito, Maurilio Ponzoni, Beatrice Greco, Marta Angiola Moresco, Matteo G. Carrabba, Fabio Ciceri, Chiara Bonini, Attilio Bondanza, Monica Casucci
Abstract
Patients with high-risk non muscle-invasive bladder cancer (NMIBC) frequently relapse after standard intravesical BCG therapy and may have a dismal outcome. Resistance mechanisms to such immunotherapy remain misunderstood. Here, using cancer cell lines, freshly resected human bladder tumors and cohorts of bladder cancer patients pre- and post-BCG therapy, we demonstrate two distinct patterns of immune subversion upon BCG relapse. In the first pattern, intracellular BCG infection of cancer cells induced a post-transcriptional downregulation of HLA-I membrane expression via an inhibition of the autophagy flux. Patients with HLA-I deficient cancer cells post-BCG therapy displayed a myeloid immunosuppressive tumor microenvironment with epithelial-to-mesenchymal transition (EMT) characteristics and dismal outcomes. Conversely, patients with HLA-I proficient cancer cells post-BCG therapy presented with CD8+ T cell tumor infiltrates, upregulation of inflammatory cytokines and inhibitory immune checkpoint molecules. Those patients had a very favorable outcome. We surmise that HLA-I expression in bladder cancers at relapse post-BCG does not result from immunoediting but rather from an immune subversion process directly induced by BCG on cancer cells, which predicts dismal prognosis. Cancer cells HLA-I scoring by immunohistochemistry (IHC) staining can be easily implemented by pathologists in routine practice in order to stratify future urothelial cancer patient treatment strategies.
Authors
Mathieu Rouanne, Julien Adam, Camélia Radulescu, Diane Letourneur, Delphine Bredel, Severine Mouraud, Anne-Gaelle Goubet, Marion Leduc, Noah Chen, Tuan Zea Tan, Nicolas Signolle, Amélie E. Bigorgne, Michael Dussiot, Lambros Tselikas, Sandrine Susini, François-Xavier Danlos, Anna K. Schneider, Roman M. Chabanon, Sophie Vacher, Ivan Bièche, Thierry Lebret, Yves Allory, Jean-Charles Soria, Nicholas Arpaia, Guido Kroemer, Oliver Kepp, Jean Paul Thiery, Laurence Zitvogel, Aurélien Marabelle
Abstract
Constant exposure of the airways to inhaled pathogens requires efficient early immune responses protecting against infections. How bacteria on the epithelial surface are detected and first-line protective mechanisms are initiated are not well understood. We have recently shown that tracheal brush cells (BC) express functional taste receptors. Here we report that bitter taste signaling in murine BC induces neurogenic inflammation. We demonstrate that BC signaling stimulates adjacent sensory nerve endings in the trachea to release the neuropeptides CGRP and Substance P that mediate plasma extravasation, neutrophil recruitment and diapedesis. Moreover, we show that bitter tasting quorum-sensing molecules from Pseudomonas aeruginosa activate tracheal BC. BC signaling depends on the key taste transduction gene Trpm5, triggers secretion of immune mediators, among the most abundant members of the complement system, and is needed to combat Pseudomonas aeruginosa infections. Our data provide functional insight into first-line defense mechanisms against bacterial infections of the lung.
Authors
Monika I. Hollenhorst, Rajender Nandigama, Saskia B. Evers, Igor Gamayun, Noran Abdel Wadood, Alaa Salah, Mario Pieper, Amanda Wyatt, Alexey Stukalov, Anna Gebhardt, Wiebke Nadolni, Wera Burow, Christian Herr, Christoph Beisswenger, Soumya Kusumakshi, Fabien Ectors, Tatjana I. Kichko, Lisa Hübner, Peter Reeh, Antje Munder, Sandra-Maria Wienhold, Martin Witzenrath, Robert Bals, Veit Flockerzi, Thomas Gudermann, Markus Bischoff, Peter Lipp, Susanna Zierler, Vladimir Chubanov, Andreas Pichlmair, Peter König, Ulrich Boehm, Gabriela Krasteva-Christ
Abstract
The relevance of molecular mechanisms governing mitochondrial proteostasis to the differentiation and function of hematopoietic and immune cells is largely elusive. Through dissection of the network of proteins related to HCLS1-associated protein X-1, we defined a potentially novel functional CLPB/HAX1/(PRKD2)/HSP27 axis with critical importance for the differentiation of neutrophil granulocytes and, thus, elucidated molecular and metabolic mechanisms underlying congenital neutropenia in patients with HAX1 deficiency as well as bi- and monoallelic mutations in CLPB. As shown by stable isotope labeling by amino acids in cell culture (SILAC) proteomics, CLPB and HAX1 control the balance of mitochondrial protein synthesis and persistence crucial for proper mitochondrial function. Impaired mitochondrial protein dynamics are associated with decreased abundance of the serine-threonine kinase PRKD2 and HSP27 phosphorylated on serines 78 and 82. Cellular defects in HAX1–/– cells can be functionally reconstituted by HSP27. Thus, mitochondrial proteostasis emerges as a critical molecular and metabolic mechanism governing the differentiation and function of neutrophil granulocytes.
Authors
Yanxin Fan, Marta Murgia, Monika I. Linder, Yoko Mizoguchi, Cong Wang, Marcin Łyszkiewicz, Natalia Ziȩtara, Yanshan Liu, Stephanie Frenz, Gabriela Sciuccati, Armando Partida-Gaytan, Zahra Alizadeh, Nima Rezaei, Peter Rehling, Sven Dennerlein, Matthias Mann, Christoph Klein
Abstract
Activated SUMOylation is a hallmark of cancer. Starting from a targeted screening for SUMO-regulated immune evasion mechanisms, we identified an evolutionarily conserved function of activated SUMOylation, which attenuated the immunogenicity of tumor cells. Activated SUMOylation allowed cancer cells to evade CD8+ T cell–mediated immunosurveillance by suppressing the MHC class I (MHC-I) antigen-processing and presentation machinery (APM). Loss of the MHC-I APM is a frequent cause of resistance to cancer immunotherapies, and the pharmacological inhibition of SUMOylation (SUMOi) resulted in reduced activity of the transcriptional repressor scaffold attachment factor B (SAFB) and induction of the MHC-I APM. Consequently, SUMOi enhanced the presentation of antigens and the susceptibility of tumor cells to CD8+ T cell–mediated killing. Importantly, SUMOi also triggered the activation of CD8+ T cells and thereby drove a feed-forward loop amplifying the specific antitumor immune response. In summary, we showed that activated SUMOylation allowed tumor cells to evade antitumor immunosurveillance, and we have expanded the understanding of SUMOi as a rational therapeutic strategy for enhancing the efficacy of cancer immunotherapies.
Authors
Uta M. Demel, Marlitt Böger, Schayan Yousefian, Corinna Grunert, Le Zhang, Paul W. Hotz, Adrian Gottschlich, Hazal Köse, Konstandina Isaakidis, Dominik Vonficht, Florian Grünschläger, Elena Rohleder, Kristina Wagner, Judith Dönig, Veronika Igl, Bernadette Brzezicha, Francis Baumgartner, Stefan Habringer, Jens Löber, Björn Chapuy, Carl Weidinger, Sebastian Kobold, Simon Haas, Antonia B. Busse, Stefan Müller, Matthias Wirth, Markus Schick, Ulrich Keller
Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)