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, et al. 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.
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.
Syndecans and glycosaminoglycans influence B-cell development and activation Craig I McKenzie, Alexandra R Dvorscek, Zhoujie Ding, Marcus J Robinson, Kristy O’Donnell, et al. 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, et al. 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.
Ki67 deficiency impedes chromatin accessibility and BCR gene rearrangement Zhoujie Ding, Maree Hagan, Feng Yan, Nick W.Y. Schroer, Jack Polmear, et al. 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.
