A Collaborative Special Issue: Highlights from the Belgian–Dutch Immunology Meeting

Abstract

On November 21–22, 2023, the third Joint Belgian–Dutch Immunology Meeting took place at the Flanders Meeting & Convention Center in Antwerp, Belgium. This event brought together over 700 researchers and clinicians from across the Netherlands and Belgium to exchange the latest insights in fundamental and translational immunology. Co-organized by the Belgian Immunological Society (BIS) and the Dutch Society for Immunology (NVVI), the meeting featured keynote lectures from international leaders in the field, including Prof. Manfred Kopf, Prof. Donna Farber, Dr. Julie Déchanet-Merville, and Prof. Georg Schett. The scientific program also included thematic parallel sessions with selected abstract presentations, poster sessions, and a dedicated Young Investigators session to highlight the work of early-career scientists. Building on the legacy of previous joint BIS–NVVI meetings held in 1988 and 2002, the 2023 edition marked a renewed commitment to cross-border collaboration and the exchange of scientific ideas between the Belgian and Dutch immunology communities.

The Belgian–Dutch Immunology Highlights special issue, inspired by the 2023 Joint Belgian–Dutch Immunology Meeting, features 20 selected original research and review articles, reflecting the scientific diversity and depth of topics presented at the meeting from fundamental insights into infection and inflammation to advances in immune regulation and emerging therapeutic strategies. Among these, we especially highlight seven articles from first-time authors: five by first-time first authors and two by first-time corresponding authors. For many of them, this marks an important milestone in their scientific careers.

Innate immune responses are not only regulated by external cues but are also modulated by sophisticated internal systems, which ensure an adequate balance between activation and suppression to preserve systemic homeostasis as well as tissue integrity.

Koops & Meyaard [1] review a lesser-known yet crucial inhibitory checkpoint in myeloid cells: the inhibitory receptor VSTM1/SIRL-1. As a pattern recognition receptor with an inhibitory function, VSTM1 suppresses the production of reactive oxygen species (ROS) and the formation of neutrophil extracellular traps (NETs) in response to both host and microbial ligands, including LL37, S100, and bacterial phenol-soluble modulins (PSMs). Its function highlights the importance of active immune dampening mechanisms, especially in contexts where the presence of pathogens does not necessitate the involvement of immune cells, such as in the skin and gut.

Parallel to this, Biscu et al. [2] illustrate how environmental cues, including dietary inputs such as vitamins and iron, microbial metabolites, and local tissue factors, shape macrophage function via metabolic rewiring. This plasticity supports both inflammatory and reparative programs and is central to the concept of macrophage niches. By targeting specific macrophage functions and metabolic processes, macrophages present a versatile target in inflammatory diseases, such as inflammatory bowel disease. Complementary findings from Ongwe et al. [2] on monocytes extend this idea across populations, showing that Sub-Saharan African individuals exhibit a distinct immunometabolic profile compared to Europeans. Enhanced pentose phosphate pathway activity in Sub-Saharan monocytes fuels higher nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and increased interleukin-10 (IL-10) production, marking a metabolically-driven and population-specific anti-inflammatory phenotype.

Naesens et al. [4] review how monogenic defects in nucleic acid sensing and type I interferon (IFN-I) signaling influence susceptibility to viral infections. Focusing on innate immune pathways, the authors highlight how both loss- and gain-of-function mutations affect antiviral defense, particularly in the context of herpesviruses, influenza, and SARS-CoV-2. These insights underscore the importance of precision immunology in identifying vulnerable populations and tailoring antiviral therapies accordingly.

Van Eyndhoven's [5] work focuses on plasmacytoid dendritic cells (pDCs), key producers of type I interferons (IFN-Is). They demonstrate that cellular decisions to initiate IFN-I production are not solely stimulus-driven but are also influenced by local cell density. pDCs act as “first responders” after pathogen recognition and initiate IFN-I production, which is amplified by autocrine signaling and by paracrine signaling to “second responders”. Importantly, low-density cultures yield a higher proportion of IFN-I producers, confirming quorum sensing as a decision-making strategy. This all-or-nothing behavior ensures that IFN-I levels are tuned to need, preventing excessive inflammation; a principle with implications for autoimmune diseases, where IFN-I pathways are frequently dysregulated.

In the context of acute inflammation, De Visscher et al. [6] studied liver-resident type 1 innate lymphoid cells (ILC1s) in a murine model of macrophage activation syndrome (MAS). Although ILC1s are activated early and produce proinflammatory cytokines such as interferon (IFN)-γ and tumor necrosis factor (TNF)-α, they rapidly undergo apoptosis, likely due to inflammation-induced mitochondrial stress, while classical NK cells (cNKs) remain largely unaffected. Using Hobit knockout mice, which lack ILC1s but retain cNKs, the study shows that the absence of ILC1s does not impact MAS progression. These findings suggest that ILC1s, despite their early activation, are dispensable for disease development, highlighting functional redundancy within the innate immune system during systemic inflammation.

Together, these studies illustrate how innate immune regulation spans inborn errors, molecular checkpoints, metabolic flexibility, population-wide communication, and functional redundancy, providing a multidimensional understanding of how the innate immune system maintains balance amid challenge.

The capacity of the immune system to distinguish between pathogenic and self-derived signals is fundamental to preserving immune homeostasis. Disruption of this equilibrium by infectious agents or sterile, damage-associated stimuli triggers immune activation, which leads to host defense as well as tissue damage.

Van Smoorenburg et al. [5] investigate how vaginal dysbiosis influences susceptibility to Human Immunodeficiency Virus type 1 (HIV-1) infection. The authors demonstrate that Prevotella timonensis, a bacterium associated with bacterial vaginosis, enhances viral uptake and transmission by mucosal dendritic cells in a subset-specific manner. Their findings highlight how host–microbe interactions at epithelial surfaces modulate viral pathogenesis, underscoring the immune consequences of microbial imbalance.

A comprehensive review by Snik et al. [8] explores the immunopathology of Lyme borreliosis, detailing the dynamic immune responses induced by Borrelia infection. They describe how distinct clinical stages, ranging from erythema migrans to neuroborreliosis and Lyme arthritis, are associated with shifts in Th1/Th2 balance, antibody responses, and autoimmune features. These insights connect infection-induced inflammation to long-term immune dysregulation and loss of tolerance.

In systemic lupus erythematosus (SLE), a prototypical autoimmune disease marked by chronic inflammation and complement activation, van der Meulen et al. [9] reveal that circulating levels of endogenous complement inhibitors correlate inversely with complement consumption, suggesting a disrupted regulatory axis. Although these inhibitors do not distinguish neuropsychiatric SLE, their levels reflect disease activity, adding nuance to the role of the complement system in SLE pathophysiology.

Rubio et al. [10] turn their attention to the central nervous system, examining the macrophage migration inhibitory factor (MIF)/CD74 axis in traumatic spinal cord injury. Drawing on both animal and human studies, they show that MIF and its receptor CD74 regulate inflammatory and reparative responses via microglia and astrocytes. Their findings position MIF/CD74 as a key mediator in balancing tissue damage and recovery following sterile injury.

In the context of atherosclerosis, Medina et al. [11] investigate the functional role of colony-stimulating factor 1 receptor (CSF1R)-expressing myeloid cells using a targeted depletion model. They find that local ablation of these cells reduces plaque burden, while systemic depletion triggers compensatory myelopoiesis and fails to impact lesion size. This study highlights the context-dependent contributions of monocytes and macrophages to vascular inflammation and remodeling.

Dyczko et al. [12] demonstrate that teriflunomide disrupts mitochondrial respiration in human FOXP3⁺ regulatory T cells by targeting complex III, leading to reduced ATP production, loss of suppressive function, and induction of a Th1-like phenotype. These findings reveal how metabolic interference can skew immune regulation and potentially exacerbate autoimmunity.

Together, these articles illustrate how immune responses, whether triggered by pathogens or tissue damage, can tip the balance between protection and pathology. The convergence of microbial cues, host-derived signals, and regulatory imbalances can drive disease across a wide range of contexts. Disentangling these intertwined pathways is essential for developing interventions that precisely modulate immunity without impairing its protective capacity.

T cells are central players in adaptive immunity, and a tight control over their mediator production is required to maintain homeostasis.

Posttranscriptional regulation, mediated by RNA-binding proteins (RBPs), allows the swift downregulation of inflammatory mediators, which contribute to autoimmune disease development when left uncontrolled. ZFP36L2 belongs to a family of RBPs that regulates T cell development, differentiation, and effector function. Using a T cell-deficient mouse model for ZFP36L2, Zandhuis et al. [13] show that, while dispensable early in activation, ZFP36L2 limits sustained IFN-γ production during chronic stimulation, providing further understanding of posttranscriptional mechanisms regulating T cell functions.

Tissue-resident memory T cells (TRM) are a specialized subset capable of long-term tissue retention and rapid response upon antigen re-exposure. These cells have the capacity to expand in vivo after antigenic stimulation. Beumer-Chuwonpad et al. [14] evaluate the possibility of expanding these cells in vitro, which would allow their use in an immunotherapy setting. They reveal that intraepithelial TRM from the small intestine expand after antigen stimulation and maintain residency gene and effector molecule expression, as well as metabolic features, when cultured in oxygen-limited conditions. This work suggests a viable approach for harnessing TRM cells in adoptive immunotherapy, particularly in mucosal tissues.

Van den Bos et al. [15] explore engineering regulatory T cells to express brain-derived neurotrophic factor (BDNF). The authors showed that despite expressing BDNF at the intracellular levels, regulatory T cell (Treg) activation was required to secrete BDNF after editing. This study contributes to understanding the mechanisms governing protein expression and secretion in engineered Tregs, offering insights for optimizing cell-based therapies and advancing immune regulation strategies.

Studying human T cells presents unique challenges compared to animal models. Access to human immune cells, especially rare or recently identified subsets, is often limited, making direct investigation difficult. Biliet et al. [16] present a novel in vitro cultivation system based on ThymoSpheres that generates CD8α T cells resembling the recently identified human αβ unconventional T cells, thereby offering an easy tool to study this emerging lineage. Accurately modeling complex cell–cell interactions, such as those involved in germinal center responses, remains a major hurdle when working with human systems.

Translating fundamental insights into therapeutic strategies requires tools that not only capture biological nuance but also support clinical applicability. Fleischmann et al. [17] review current efforts to model the human germinal center response and provide an overview of existing 2D and 3D in vitro and ex vivo human models of the germinal center reaction. While useful for the study of T–B cell interactions, the authors highlight that these models are currently unable to fully replicate the human GC process and that more physiologically relevant systems to study T–B cell interactions should be developed.

Together, these studies provide new insights into the regulation, modeling, and manipulation of T cells and expand the experimental and conceptual tools available for studying T cells in both basic and translational contexts.

Despite the major advances of immunotherapy, immune evasion remains a defining hallmark of solid tumors. Cancer cells actively reshape the immune microenvironment, using mechanisms ranging from checkpoint modulation to remodeling of the cell surface glycocalyx. Among these, changes in glycosylation patterns have emerged as a powerful strategy to impair both innate and adaptive immune recognition.

In this context, Rodriguez [18] provides an overview of how aberrant tumor glycosylation contributes to immune escape. The review highlights how specific glycosylation patterns, such as fucosylation, truncated O-glycans, and hypersialylation, interact with inhibitory lectin receptors like Siglecs (sialic acid-binding immunoglobulin-like lectins) and DC-SIGN (a dendritic cell-specific C-type lectin receptor). These altered glycan structures generate an immunosuppressive glyco-code, blunting both innate sensing and T-cell activation. While glycan-targeted therapies are largely preclinical, early clinical trials targeting tumor-associated glycans are underway, highlighting the translational potential of this strategy.

Building on these broader concepts, two original studies in this issue provide mechanistic insights into tumor-driven immune modulation. Subtil et al. [19] investigate how soluble tumor factors actively reprogram dendritic cells within the tumor microenvironment. Using a colorectal cancer organoid model, they show that tumor-derived IL-6 and prostaglandin E2 drive conventional dendritic cells (cDC2s) into a dysfunctional DC3-like phenotype, characterized by impaired T cell stimulation. These findings reveal that tumors do not merely suppress immunity passively but actively subvert key antigen-presenting cells. Whether such reprogramming is reversible remains an important open question, with direct implications for therapeutic strategies aimed at restoring dendritic cell function in cancer. Verkerk et al. [20] focus on intrinsic changes in tumor cell surface glycosphingolipids. They demonstrate that the intramembrane protease SPPL3 restrains the accumulation of neolacto-series glycosphingolipids (nsGSLs), structures that otherwise shield tumor cells from γδ T cell- and neutrophil-mediated cytotoxicity. By directly modulating glycan composition, tumors diminish their visibility to innate immune effectors. Although targeting glycosylation presents clear therapeutic potential, translating these findings into clinical interventions will require approaches that selectively remodel tumor glycans without disrupting normal tissue homeostasis.

Together, these studies emphasize that tumors orchestrate immune escape through coordinated, multilayered strategies, combining cytokine-driven immune cell reprogramming and glycan-mediated immune suppression. Future therapeutic approaches will need to address these interconnected pathways to more effectively overcome tumor immune evasion. Integrating glycobiology into mainstream immuno-oncology will be crucial to achieving broader, more durable responses in cancer patients.