Immunology, Cell Biology, Molecular Biology, Molecular Medicine
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Scopus Publications
Scopus Publications
CD8 T Cell Sensing of Type I Interferon Impacts Anergy Anne S. Haefke, Hanna Gröber, Ioana Sandu, Vanessa Skipness, Nikos Pantouloufos, Fabienne Gräbnitz, Marie‐Elen Tuchel, Nathan Zangger, Dominique Stark, Marvin Kříž, Carmine Cristinzio, Hanspeter Pircher, Roman Spörri, Isaak Quast, Annette Oxenius European Journal of Immunology, 2026 Peripheral tolerance is indispensable for the maintenance of immune homeostasis, allowing protective immunity while limiting responses to self‐antigens. CD8 T cells activated in the absence of co‐stimulation and pro‐inflammatory cytokines are either deleted, rendered anergic, or actively suppressed. These mechanisms are well established, but the cues determining the mode and depth of peripheral tolerance remain incompletely understood. Here, we identify type I interferon (IFN‐I) signalling in T cells as a key modulator of peripheral tolerance in the absence of infection. In the complete absence of IFN‐I signalling, autoreactive CD8 T cells are rendered anergic, and their expansion, phenotype and function are tightly controlled. Basal levels of IFN‐I are sufficient for self‐reactive CD8 T cells to expand and retain partial effector functions in the absence of viral infections. This is dependent on T cell‐intrinsic IFN‐I sensing and is associated with the generation of a partially anergic, TCF1 + CD8 T cell subset that can contribute to a pathogen‐specific immune response. Collectively, our results suggest that elevated basal IFN‐I levels limit anergy induction, providing a potential mechanistic explanation for the association of baseline inflammation with the development of autoimmunity.
Antibody responses against bacterial glycans affinity mature and diversify in germinal centers Holly A. Fryer, Catherine Pitt, Hannah R. Frost, Nitika Kandhari, Sean Byars, Pailene S. Lim, Rhiannon L. Fettes, Reece M. Lovett, Trang T. Nguyen, Kaneka Chheng, Natalie Caltabiano, Alana L. Whitcombe, Julianne Hamelink, Dean Andrew, Gareth Lloyd, Brian Wilson-Boyd, Nicola Slee, Jodie Ballantine, Sarju Vasani, Kathryn Girling, Liam Gubbels, Eric Levi, Karen Davies, Stuart G. Tangye, Jonathan Noonan, Nicole J. Moreland, Isaak Quast, Marcus J. Robinson, Stephen W. Scally, Melanie R. Neeland, Shivanthan Shanthikumar, Joshua Osowicki, David M. Tarlinton, Andrew C. Steer, Michelle J. Boyle, Danika L. Hill Immunity, 2026 Anti-carbohydrate antibodies (Abs) play crucial roles in pathogen control, but their generation remains poorly understood. Here, we studied how B cell immunity against the Streptococcus pyogenes surface polysaccharide is influenced by age and antigen (Ag) exposure across human blood, spleen, and tonsils. The glycan-targeted response shifted from immunoglobulin M (IgM) biased in children toward IgG and IgA biased in adults. Both natural colonization and controlled human infection with S. pyogenes increased class-switched B cells, with evidence of within-clone switching. Glycan-specific B cells readily engaged in germinal center (GC) responses and underwent robust somatic hypermutation (SHM) but had reduced expression of T cell help-associated molecules, correlating with lower antibody-secreting cell (ASC) output. Thus, mucosal pathogen encounters elicit glycan responses that class switch, evolve, and diversify through the GC, with implications for the design and schedule of glycan-containing vaccines.
B Cell Selection in Antibody Production: Affinity Rules, but Diversity Matters Isaak Quast, David M. Tarlinton Annual Review of Immunology, 2026 Affinity for antigen is a fundamental parameter of humoral immunity. It determines the B cell clones that participate in the response, it is a readout of clonal selection as the response progresses, and the magnitude of its improvement in T cell–dependent responses is a major criterion of success. But another important attribute of immunity at initiation, propagation, and cessation is the diversity of antigen binding by B cells and antibodies. As such, the diversity of antigen receptors is important at the outset of the response in providing a broad population from which B cell fates can be selected. Equally, within the germinal center, specific mechanisms operate to diversify the B cell population for affinity-based selection, which itself promotes clonal restriction to achieve its goals. However, the importance of sustaining diversity of antigen recognition at all stages of the response, not only in the composition of the B cell memory compartments, is often lost by the focus on affinity as the key measure of immunity. In this article, we consider recent developments in understanding B cell selection into, persistence within, and exit from T cell–dependent immune responses and how these processes are calibrated to ensure diversity of antigen recognition persists into memory in spite of the clonal narrowing that is the usual outcome of affinity-driven selection.
Long-lived IgE plasma cells persist in secondary lymphoid tissues using a navitoclax-sensitive survival program Zhoujie Ding, Mark R. Dowling, Adam K. Wade-Vallance, Alexandra R. Dvorscek, Catherine Pitt, Jesse Mulder, Kristy O’Donnell, Craig McKenzie, Alexandra Bosak Karaviotis, Julia Scrofani, Olaf Perdijk, Danika L. Hill, Isaak Quast, David M. Tarlinton, Christopher D.C. Allen, Marcus J. Robinson Immunity, 2025 than MCL1. Thus, continual production of short-lived IgE ASCs and retention of long-lived IgE ASCs outside the BM together drive IgE persistence, perpetuating allergic disease.
Syndecans and glycosaminoglycans influence B-cell development and activation Craig I McKenzie, Alexandra R Dvorscek, Zhoujie Ding, Marcus J Robinson, Kristy O’Donnell, Catherine Pitt, Daniel T Ferguson, Jesse Mulder, Marco J Herold, David M Tarlinton, Isaak Quast EMBO Reports, 2025 Syndecans (SDCs) are glycosaminoglycan-containing cell surface proteins with diverse functions in the immune system with SDC1 (CD138) and SDC4 expressed in B-lineage cells. Here, we show that stem cells lacking either molecule generate fewer B-cell progenitors but give rise to mature B cells in vivo. Deletion of the plasma cell “marker” CD138 has no effect on homeostatic or antigen-induced plasma cell formation. Naive B cells express high SDC4 and encounter with cognate antigen results in transient CD138 upregulation and SDC4 loss, both further modulated by IL-4, IL-21, and CD40 ligation. SDC4 is downregulated on germinal center B cells and absent on most memory B cells. Glycosaminoglycans such as those attached to SDCs, and heparin, a commonly used therapeutic, regulate survival and activation of naive B cells by limiting responsiveness to cognate antigen. Conversely, ablation of SDC4 results in increased baseline and antigen-induced B-cell activation. Collectively, our data reveal B-cell activation- and subset-dependent SDC expression and show that SDC4 and GAGs can limit antigen-induced activation to promote B-cell survival and expansion.
Single-Cell Transcriptomics Identifies a Prominent Role for the MIF-CD74 Axis in Myasthenia Gravis Thymus Paula Terroba-Navajas, I-Na Lu, Isaak Quast, Michael Heming, Christian W. Keller, Lennard Ostendorf, Anja Erika Hauser, Ronja Mothes, Helena Radbruch, Frauke Stascheit, Andreas Georg Otto Meisel, Heinz Wiendl, Gerd Meyer Zu Hörste, Nick Willcox, Jan D. Lünemann Neurology Neuroimmunology and Neuroinflammation, 2025 Background and Objectives Myasthenia gravis (MG) is an autoimmune disease most frequently caused by autoantibodies (auto-Abs) against the acetylcholine receptor (AChR) located at the neuromuscular junction. Thymic follicular hyperplasia is present in most of the patients with early-onset AChR-Ab+ MG (EOMG), but its cellular and molecular drivers and development remain poorly understood. Methods We constructed a single cell-based transcriptional profile of lymphoid cell types in thymi from 11 immunotherapy-naïve patients with EOMG. Multiplex histology and ELISA were used to determine migration inhibitory factor (MIF) levels. Results Within EOMG thymi, we consistently observed 6 distinct clusters of B-cell populations maturing toward germinal center (GC)–associated and Ab-secreting cells, featuring prominent GC activity, as indicated by substantial clonal expansions and cycling B-cell subsets. Cell-cell interactome predictions identified strong interactions between T cells and GC-associated and memory B cells, dominated by B-cell prosurvival signaling through the MIF-CD74 axis. Multiplex histology confirmed abundant expression of CD74 in MG thymic B cells. Circulating MIF levels in EOMG correlated with higher disease severity as assessed by Myasthenia Gravis Foundation of America status. Discussion Our data not only illustrate and define hyperplastic thymic niches in MG as favorable environments for pathogenic B-cell proliferation, maturation, and persistence but also suggest that the MIF-CD74 axis should be investigated for potential novel therapeutic targeting in EOMG.
Conversion of vaccines from low to high immunogenicity by antibodies with epitope complementarity Alexandra R. Dvorscek, Craig I. McKenzie, Vera C. Stäheli, Zhoujie Ding, Jacqueline White, Stewart A. Fabb, Leonard Lim, Kristy O’Donnell, Catherine Pitt, Daniel Christ, Danika L. Hill, Colin W. Pouton, Deborah L. Burnett, Robert Brink, Marcus J. Robinson, David M. Tarlinton, Isaak Quast Immunity, 2024
Ki67 deficiency impedes chromatin accessibility and BCR gene rearrangement Zhoujie Ding, Maree Hagan, Feng Yan, Nick W.Y. Schroer, Jack Polmear, Kim L. Good-Jacobson, Alexandra R. Dvorscek, Catherine Pitt, Kristy O’Donnell, Stephen L. Nutt, Dimitra Zotos, Craig McKenzie, Danika L. Hill, Marcus J. Robinson, Isaak Quast, Frank Koentgen, David M. Tarlinton Journal of Experimental Medicine, 2024 The proliferation marker Ki67 has been attributed critical functions in maintaining mitotic chromosome morphology and heterochromatin organization during the cell cycle, indicating a potential role in developmental processes requiring rigid cell-cycle control. Here, we discovered that despite normal fecundity and organogenesis, germline deficiency in Ki67 resulted in substantial defects specifically in peripheral B and T lymphocytes. This was not due to impaired cell proliferation but rather to early lymphopoiesis at specific stages where antigen–receptor gene rearrangements occurred. We identified that Ki67 was required for normal global chromatin accessibility involving regulatory regions of genes critical for checkpoint stages in B cell lymphopoiesis. In line with this, mRNA expression of Rag1 was diminished and gene rearrangement was less efficient in the absence of Ki67. Transgenes encoding productively rearranged immunoglobulin heavy and light chains complemented Ki67 deficiency, completely rescuing early B cell development. Collectively, these results identify a unique contribution from Ki67 to somatic antigen–receptor gene rearrangement during lymphopoiesis.
EBV renders B cells susceptible to HIV-1 in humanized mice Donal McHugh, Renier Myburgh, Nicole Caduff, Michael Spohn, Yik Lim Kok, Christian W Keller, Anita Murer, Bithi Chatterjee, Julia Rühl, Christine Engelmann, Obinna Chijioke, Isaak Quast, Mohaned Shilaih, Victoria P Strouvelle, Kathrin Neumann, Thomas Menter, Stephan Dirnhofer, Janice KP Lam, Kwai F Hui, Simon Bredl, Erika Schlaepfer, Silvia Sorce, Andrea Zbinden, Riccarda Capaul, Jan D Lünemann, Adriano Aguzzi, Alan KS Chiang, Werner Kempf, Alexandra Trkola, Karin J Metzner, Markus G Manz, Adam Grundhoff, Roberto F Speck, Christian Münz Life Science Alliance, 2020
IVIG regulates the survival of human but not mouse neutrophils Christoph Schneider, Simone Wicki, Stefanie Graeter, Tankica M. Timcheva, Christian W. Keller, Isaak Quast, Danila Leontyev, Iglika K. Djoumerska-Alexieva, Fabian Käsermann, Stephan M. Jakob, Petya A. Dimitrova, Donald R. Branch, Richard D. Cummings, Jan D. Lünemann, Thomas Kaufmann, Hans-Uwe Simon, Stephan von Gunten Scientific Reports, 2017
Persistent KSHV Infection Increases EBV-Associated Tumor Formation In Vivo via Enhanced EBV Lytic Gene Expression Donal McHugh, Nicole Caduff, Mario Henrique M. Barros, Patrick C. Rämer, Ana Raykova, Anita Murer, Vanessa Landtwing, Isaak Quast, Christine T. Styles, Michael Spohn, Adeola Fowotade, Henri-Jacques Delecluse, Alexandra Papoudou-Bai, Yong-Moon Lee, Jin-Man Kim, Jaap Middeldorp, Thomas F. Schulz, Ethel Cesarman, Andrea Zbinden, Riccarda Capaul, Robert E. White, Martin J. Allday, Gerald Niedobitek, David J. Blackbourn, Adam Grundhoff, Christian Münz Cell Host and Microbe, 2017
Sialylation of IgG Fc domain impairs complement-dependent cytotoxicity Isaak Quast, Christian W. Keller, Michael A. Maurer, John P. Giddens, Björn Tackenberg, Lai-Xi Wang, Christian Münz, Falk Nimmerjahn, Marinos C. Dalakas, Jan D. Lünemann Journal of Clinical Investigation, 2015
