eLife: latest articles by subject

Heterozygote advantage cannot explain MHC diversity, but MHC diversity can explain heterozygote advantage

jcherry@ncbi.nlm.nih.gov (Joshua L Cherry) — Mon, 13 Jul 2026 00:00:00 +0000

Several theoretical studies have concluded that heterozygote advantage makes at most a minor contribution to MHC diversity. Siljestam and Rueffler (2024) recently presented models in which heterozygote advantage alone can lead to realistically high diversity. Here I argue that heterozygote advantage cannot by itself explain MHC diversity, and that its contribution to diversity is unlikely to be large in most species. I first show that the high diversity reported by Siljestam and Rueffler is so sensitive to parameter values that the underlying phenomenon cannot explain the widespread diversity of MHC genes. I then consider a fundamental problem with explaining MHC diversity by heterozygote advantage alone: selective forces that favored heterozygotes would lead to the evolution of haplotypes having much higher fitness when homozygous, diminishing or eliminating heterozygote advantage. Diversity maintained by another force, however, might bring about adaptation to the more common heterozygous state at the expense of homozygous fitness. Thus, substantial heterozygote advantage may arise as a consequence of MHC diversity.

TGF-β drives the conversion of conventional NK cells into uterine tissue-resident NK cells to support murine pregnancy

yokoyama@wustl.edu (D Michael Nelson) — Wed, 08 Jul 2026 00:00:00 +0000

Tissue microenvironments shape lymphocyte differentiation to align immune function with local physiological demands. Uterine natural killer (NK) cells are critical for reproductive success, yet the molecular cues in the uterus that instruct their specialized identities remain incompletely understood. Here, we identify a TGF-β-dependent differentiation pathway by which circulating conventional NK cells convert into uterine tissue-resident NK cells during murine pregnancy. Loss of TGF-β receptor II expression in Ncr1-expressing cells disrupted this conversion, markedly reducing tissue-resident NK cells in the gravid uterus. Impaired TGF-β-driven uterine tissue-resident NK cell differentiation during murine pregnancy led to abnormal spiral artery remodeling and increased fetal resorption rates at mid-gestation, ultimately reducing litter sizes at birth. Collectively, these findings define TGF-β as a pivotal driver of tissue-resident NK cell differentiation in the gravid uterus and establish a mechanistic framework through which the uterine microenvironment programs NK cell identity to meet the physiological demands of gestation.

Depletion of extracellular asparagine impairs self-reactive T cells and ameliorates autoimmunity in a murine model of multiple sclerosis

marcia_haigis@hms.harvard.edu (Arlene H Sharpe) — Wed, 08 Jul 2026 00:00:00 +0000

Amino acids play critical roles in the activation and function of lymphocytes. Here we show that the non-essential amino acid, asparagine, is essential for optimal activation and proliferation of CD4⁺ T cells. We demonstrate that asparagine depletion at different time points after CD4⁺ T cell activation reduces mitochondrial membrane potential and function. Furthermore, asparagine depletion at specific time points during CD4⁺ T cell differentiation reduces cytokine production in multiple CD4⁺ T cell subsets. In an adoptive transfer model of experimental autoimmune encephalomyelitis (EAE), myelin oligodendrocyte-specific pathogenic T helper 17 cells differentiated under Asn-deficient conditions exhibited reduced encephalitogenic potential and attenuated EAE severity. In a model of EAE induced by active immunization, therapeutic depletion of extracellular Asn significantly reduced disease severity. These results identify asparagine as a key metabolic regulator of the pathogenicity of autoreactive CD4⁺ T cells and suggest that targeting asparagine metabolism may be a novel therapeutic strategy for autoimmunity.

Cribriform plate microenvironment assembles a suppressive myeloid network during EAE-induced neuroinflammation

zfabry@wisc.edu (Andy Madrid) — Wed, 08 Jul 2026 00:00:00 +0000

During neuroinflammation, CD11c⁺CD11b⁺ myeloid cells accumulate at the cribriform plate, a key cerebrospinal fluid and antigen outflow site in mice. At this site, podoplanin-expressing cells, including lymphatic vessels and meningeal layers, expand to create a distinct drainage microenvironment. In this study, we sought to characterize myeloid cells, which populate this region, using a mouse model of neuroinflammation, experimental autoimmune encephalomyelitis. Utilizing a combination of immunohistochemistry, flow cytometry, and scRNAseq, we report that macrophages and dendritic cells from this region display unique expressional signatures related to tolerance, cell death, and reduced inflammatory profile. Together, this data supports that myeloid retention at the cribriform plate and olfactory bulb meninges promotes a local immunosuppressive environment.

Celldetective, an AI-enhanced image analysis tool for unraveling dynamic cell interactions

remy.torro@gmail.com (Beatriz Díaz-Bello) — Wed, 08 Jul 2026 00:00:00 +0000

Analysis of multimodal and multidimensional data capturing dynamic interactions between diverse cell populations is a current challenge in bioimaging, especially in the context of immunology and immunotherapy research. Here, we introduce Celldetective, an open-source Python-based software tool designed for high-performance end-to-end analysis of image-based in vitro immune and immunotherapy assays. Celldetective is purpose-built for multicondition, 2D multi-channel time-lapse microscopy of mixed cell populations. Although it is optimised for the needs of immunology assays, it is nevertheless broadly applicable to any biological system involving interacting cell populations. The software seamlessly integrates AI-based segmentation, tracking, and automated single-cell event detection, all within an intuitive graphical interface that supports interactive visualisation, annotation, and training options. We showcase its capabilities with original datasets of single immune effector cell interactions with an activating surface mediated by bispecific antibodies and pairwise interactions in antibody-dependent cell cytotoxicity events.

Pink1-mediated mitophagy in the endothelium releases proteins encoded by mitochondrial DNA and activates neutrophil responses during inflammation

jalees@uic.edu (Chinnaswamy Tiruppathi) — Wed, 01 Jul 2026 00:00:00 +0000

Eukaryotic mitochondria are characterized by several features that represent vestiges of their prokaryotic ancestry. One such feature is the N-terminal formylation of proteins encoded by mitochondrial DNA that undergo translation by mitochondrial ribosomes. N-formylated proteins are also released by bacteria and trigger activation of immune cells such as neutrophils. Growing evidence indicates that circulating levels of mitochondrial formyl proteins are elevated in the serum of patients with excessive inflammatory responses. However, the mechanisms by which they are released into circulation are not known. In this study, we have identified vascular endothelial cells as a source of Pink1-dependent release of mitochondrial formyl proteins in response to inflammatory mediators. Mechanistically, the mitophagy mediator Pink1 is stabilized by inflammatory activation of endothelial cells, promoting mitophagy and mitochondrial formyl peptide release both in mice and primary human endothelial cells. Using nanoparticle delivery of Pink1-targeting sgRNA in mice expressing endothelial-specific Cas9, we developed a mouse model in which Pink1 is specifically depleted in the endothelium. Deletion of endothelial Pink1 decreased circulating formyl peptide levels, lowered lung neutrophil infiltration and reduced mortality in mice. We thus propose that endothelial cells upregulate pro-inflammatory mitophagy in response to inflammation, leading to the release of mitochondrial formyl peptides and detrimental neutrophil recruitment into the lung.

Direct contact between iPSC-derived macrophages and hepatocytes drives reciprocal acquisition of Kupffer cell identity and hepatocyte maturation

phsyuh@nus.edu.sg (Christopher Zhe Wei Lee) — Mon, 29 Jun 2026 00:00:00 +0000

As the resident tissue macrophage of the liver, Kupffer cells (KCs) play an important role in homeostasis and tissue support. However, current in vitro liver models often ignore the contribution of these KCs towards the proper response and function of the tissue. This is especially relevant when we consider the implications of immune-mediated drug injuries. To address this issue, we developed an isogenic co-culture system utilising iPSC-derived macrophages (iMacs) and hepatocytes (iHeps). Directly co-culturing iHeps with iMacs improved the differentiation and maturation of the iHeps, with significant downregulation of fetal hepatocyte markers as well as upregulation of cytochrome genes. Furthermore, the co-culture also imparted stronger KC identity to the iMacs in a contact-dependent manner, with iMacs cultured in iHep conditioned media alone showing weaker expression of key KC markers. Finally, challenging the iHep-iMac co-culture system with seven paradigm hepatotoxic compounds showed dose-dependent cytokine response in the five compounds associated with immune-mediated liver injuries while no significant changes were observed in the two compounds with no reported immune-dependent complications. This effect was also not recapitulated when the co-culture was instead performed with human peripheral blood monocyte-derived macrophages, suggesting that iMacs are essential for liver toxicity response. Taken together, our study shows not only the importance of macrophages in tissue systems, but also that the source of macrophages is critical to the development of accurate in vitro human models.

Correlates of protection against African swine fever virus identified by a systems immunology approach

artur.summerfield@unibe.ch (Artur Summerfield) — Mon, 29 Jun 2026 00:00:00 +0000

African swine fever virus (ASFV) causes a fatal hemorrhagic disease in domestic pigs and wild boars, which poses severe threats to the global pork industry. Despite the promise of live attenuated vaccines (LAVs), their narrow margin between efficacy and residual virulence presents major safety challenges. This study bridges a critical knowledge gap in ASF vaccinology by identifying innate and adaptive correlates of protection. This was achieved by using an established model with two groups of pigs differing in baseline immunological status (farm and specific pathogen-free [SPF]). The animals were immunized with an attenuated ASFV strain and subsequently challenged with a related, highly virulent genotype II strain. By applying a systems immunology approach, we correlated kinetic data, including serum cytokines, blood transcription modules (BTMs), T-cell responses, and antibody levels, with clinical outcomes to track protective and detrimental immune responses to the virus over time. Key innate correlates of protection included early and sustained IFN-α response, activation of antigen presentation BTMs, and controlled IL-8 levels during immunization. Lower baseline immune activation observed in SPF pigs in steady state was linked to increased protection. Adaptive correlates encompassed cell cycle, plasma cell, and T-cell BTM responses lasting until day 15 post-immunization. Consequently, an effective response from ASFV-specific T_h cells prior to challenge indicated protection. After the challenge, an early IFN-α response, along with low levels of pro-inflammatory cytokines and a strong induction of memory T_h and T_c cells, correlated with improved clinical outcomes. The model highlights the critical role of host-specific factors in vaccine efficacy and provides a valuable framework for optimizing ASFV vaccine design while distinguishing between protective and detrimental immune responses.

Deciphering interferon functions in avian influenza using receptor knockout models in the natural host

benjamin.schusser@tum.de (Arne Reich) — Fri, 26 Jun 2026 00:00:00 +0000

The rapid cross-species transmission of highly pathogenic avian influenza presents a significant zoonotic threat. Elucidating the avian interferon (IFN) system, the primary antiviral defense in chickens, is critical for controlling the virus at its source and preventing its spillover into humans and other species. We engineered type I (IFN-α/β) and type III (IFN-λ) IFN receptor knockout chickens to dissect the role of IFNs in viral infections. Results revealed that type I IFN predominantly modulates innate immune cell populations, T cell subsets, and their contribution to antibody production following immunization under physiological conditions. In ovo and in vivo challenge experiments utilizing diverse influenza A virus strains demonstrated strain-specific roles of both IFN-α/β and IFN-λ in orchestrating viral pathogenesis, immunological responses, and tissue-tropism effects. Notably, type I IFN was particularly crucial in the initial defense mechanisms against H3N1 avian influenza A virus infection. These novel models offer unprecedented insights into avian IFN biology within the context of avian influenza, which is essential for developing more effective strategies to prevent and control this public health challenge.

Metabolic support of trained immune responses in myeloid cells

gillian.dunphy@cnic.es (Aitor Jarit-Cabanillas) — Fri, 19 Jun 2026 00:00:00 +0000

Trained immunity (TI) is defined as a form of innate immune memory characterised by a long-lasting ability to develop enhanced responses to a secondary challenge, whether of the same or a different nature than the initial stimulus. This process is mediated by several established hallmarks, most prominently the existence of activating epigenetic marks and metabolic adaptations. The activating epigenetic marks prime the expression of immune-related genes and are a direct driving force behind the increased cytokine production after secondary stimulation of trained monocytes and macrophages. Training stimuli also induce specific metabolic adaptations, such as the upregulation of glycolysis and lactate production or the activation of glutaminolysis leading to fumarate accumulation, which in turn promotes epigenetic changes. However, the mechanisms linking these epigenetic and metabolic changes to a TI phenotype are varied, and not all stimuli that increase glycolysis promote training, whereas some stimuli such as lipopolysaccharide (LPS) display a non-monotonic induction of TI. In addition to metabolism directly driving epigenetic changes, early gene expression changes can also reshape cell metabolism to promote a trained phenotype. In this review we aim to separate two main types of metabolic rewiring that have not been previously uncoupled. Firstly, those primary metabolic changes occurring during the initial stimulation, which precede TI induction by altering the epigenomic landscape around inflammatory genes. Secondly, those metabolic adaptations arising later as a consequence of the first wave of epigenetic regulation, which support an enhanced functional state of macrophages.

Tracheal terminal cells of Drosophila are immune privileged to maintain their Foxo-dependent structural plasticity

jbossen@zoologie.uni-kiel.de (Jingjing He) — Wed, 17 Jun 2026 00:00:00 +0000

Respiratory organs must balance their primary function of gas exchange with the constant threat of inhaled pathogens. In the Drosophila tracheal system, gas exchange occurs at the tracheal terminal cells (TTCs), the functional equivalents of mammalian alveoli. While bacterial infection triggers a robust innate immune response throughout the broader airway epithelium, we reveal that TTCs are uniquely exempt from this reaction. Mechanistically, TTCs lack expression of the membrane-associated peptidoglycan recognition receptor PGRP-LC. This absence protects these highly susceptible cells from immune deficiency (Imd) pathway activation and subsequent JNK-mediated cell death, establishing TTCs as a distinct, immune-privileged niche. Ectopic immune activation via targeted PGRP-LCx overexpression in TTCs caused a severe reduction in branching, cellular damage, and ultimately cell death, phenotypes that were fully rescued by the depletion of AP-1 or foxo. Because both structural plasticity (in response to nutritional cues and hypoxia) and innate immune responses strictly require the transcription factor FoxO, we demonstrate that potent immune signaling is fundamentally incompatible with dynamic TTC remodeling. Ultimately, the immune-privileged status of TTCs represents an essential evolutionary trade-off, restricting local inflammation to preserve foxo-dependent structural plasticity and vital respiratory function.

Deep mutational scanning reveals pharmacologically relevant insights into TYK2 signaling and disease

diane@octant.bio (Abhay Hukku) — Wed, 10 Jun 2026 00:00:00 +0000

Tyrosine kinase 2 (TYK2) is a genetically defined target for autoimmune disease, with first-generation inhibitors showing clinical success in some but not all associated indications. A deeper understanding of TYK2 structure-function relationships, protein-ligand interactions, and the impact of human variants could inform next-generation therapeutics. Here, we applied deep mutational scanning (DMS) to assess >23,000 amino acid substitutions across two TYK2 functions: interferon alpha (IFN-α) signaling and protein abundance. This enabled high-resolution structure-function mapping and the identification of novel allosteric sites. By coupling DMS with inhibitor treatment, we uncovered variants that modulate compound potency. We also show that human variants – both common and rare – that are protective against autoimmune phenotypes reduce TYK2 protein abundance. Together, these findings demonstrate that DMS can prospectively reveal novel druggable sites, clarify structure-activity relationships (SAR), and highlight TYK2 degradation as a potential therapeutic strategy in autoimmunity.

Beta-Glucan modulates monocyte plasticity and differentiation capacity to mitigate DSS-induced colitis

jianlin.ren@126.com (Dan Du) — Mon, 01 Jun 2026 00:00:00 +0000

Trained immunity involves the reprogramming of innate immune cells after an initial exposure, resulting in heightened inflammatory responses to subsequent stimuli and enhanced bactericidal capacity during infection. However, this pro-inflammatory state could also exacerbate chronic conditions like inflammatory bowel disease (IBD), which is characterized by persistent inflammation and microbial imbalance. It remains unclear how trained immunity influences IBD pathogenesis and whether it can be harnessed therapeutically. In our study, pretreatment with β-glucan reprogrammed bone marrow hematopoietic progenitors and peripheral monocytes, inducing a profound shift in monocyte plasticity and significantly reducing the severity of dextran sulfate sodium (DSS)-induced colitis. Adoptive transfer of bone marrow or peripheral monocytes from β-glucan-trained mice into naive mice conferred robust protection against colitis, demonstrating that this protective effect is transferable. Trained mice also displayed improved clearance of intestinal bacterial infections. Single-cell RNA sequencing revealed an expansion of reparative Cx3cr1⁺ macrophages derived from Ly6C^hi monocytes, correlating with accelerated colonic epithelial regeneration. Collectively, these findings reveal how β-glucan-induced trained immunity modulates monocyte differentiation to ameliorate experimental colitis, highlighting the potential of harnessing trained immunity as a therapeutic strategy to recalibrate innate immune responses and restore gut homeostasis in IBD, shedding light for future clinical applications.

Lipopolysaccharide stimulates dynamic changes in B cell metabolism to promote proliferation

j.s.c.arthur@dundee.ac.uk (Andrew JM Howden) — Thu, 21 May 2026 00:00:00 +0000

Naive B cells exit quiescence and enter a proliferative state upon activation, ultimately differentiating into antibody-secreting or memory B cells. Toll-like receptor (TLR) ligands, such as lipopolysaccharide (LPS), can serve as physiological stimuli to initiate this transition. Using quantitative proteomics, we show that TLR4 engagement induces metabolic reprogramming in murine B cells, increasing the expression of amino acid transporters and cholesterol biosynthetic enzymes. The amino acid transporter SLC7A5 is markedly upregulated following LPS stimulation, and conditional deletion of Slc7a5 impairs B cell proliferation, underscoring its essential role in B cell activation. LPS also elevates intracellular cholesterol levels, and inhibition of the rate-limiting enzyme HMG-CoA reductase blocks proliferation. This effect was mediated by a dual requirement for cholesterol metabolism and protein prenylation downstream of HMG-CoA reductase. Notably, this was not unique to TLR4 signalling but is also observed in B cells activated via TLR7, TLR9, CD40, or the B cell receptor. Together, these findings reveal that metabolic rewiring, including amino acid uptake and cholesterol metabolism, is an essential feature of B cell activation and proliferation.

Redirection of SARS-CoV-2 to phagocytes by intranasal sACE2-Fc as a universal decoy confers complete prophylactic protection

llmpoon@hku.hk (Alex WH Chin) — Mon, 18 May 2026 00:00:00 +0000

The rapid evolution of SARS-CoV-2 and other respiratory RNA viruses limits the success of current vaccines and antibody-based therapies. Engineered decoy receptors based on soluble angiotensin-converting enzyme 2 (sACE2) offer promising alternatives but show limited clinical success. This study conducted functional and mechanistic analyses using an optimized sACE2 mutant fused to human IgG1 Fc (B5-D3) as a representative, revealing redirection of virus–decoy complexes from epithelial infection to lysosomal degradation in phagocytes beyond viral neutralization. Intranasal prophylactic delivery of B5-D3 confers complete protection in SARS-CoV-2-infected K18-hACE2 mice, regardless of age. Abrogation of Fc effector functions compromises antiviral protection, indicating that Fc-mediated uptake of virus–decoy complexes is critical. Transcriptomic analysis suggests that B5-D3 induces early immune activation in the lungs of infected mice. Bio-distribution and flow cytometry reveal selective targeting of airway phagocytes. In vitro assays confirm lysosomal degradation of virus–decoy complexes by macrophages without productive infection. These findings reveal a distinct antiviral mechanism via phagocytic clearance, supporting refined regimens for decoy treatments against SARS-CoV-2 and potentially other respiratory viruses.

Cas9⁺ conditionally immortalized neutrophil progenitors as a tool for genome-wide CRISPR screening for neutrophil differentiation and function

sastanley@berkeley.edu (Alex Zilinskas) — Mon, 18 May 2026 00:00:00 +0000

Neutrophils are short-lived cells of the innate immune system that play numerous roles in defense against infection, regulation of immune responses, tissue damage and repair, autoimmunity, and other non-communicable diseases. Understanding neutrophil function at a mechanistic level has been hampered by the difficulty of working with primary neutrophils, which die rapidly upon isolation, and the relative paucity of neutrophil cell lines. Here, we report the creation of a Cas9 +ER-Hoxb8 neutrophil progenitor cell line that enables both forward and reverse genetic analysis of neutrophils. By editing progenitors via transduction with sgRNAs and then withdrawing estrogen, Cas9-edited neutrophils are produced with high efficiency. Importantly, neutrophil differentiation of edited progenitors occurs both in vitro in cell culture and when transferred into murine recipients. To demonstrate the utility of Cas9 +ER-Hoxb8 progenitors for forward genetics, we performed a pooled CRISPR screen to identify factors required for survival during neutrophil differentiation. This screen identified hundreds of genes, including Cebpe, a transcription factor known to be required for neutrophil differentiation from pre-neutrophils to immature neutrophils. Using this progenitor cell line, we confirmed that Cebpe is required for neutrophil differentiation in vivo, validating the utility of this line for studying in vivo phenotypes. The screen also identified all components of the WASH complex as being required for neutrophil differentiation, extending its known role in hematopoietic stem cell differentiation to later stages of neutrophil development. Taken together, this resource enables the analysis of the role of neutrophils in numerous disease states using genetics for the first time.

Intravital calcium imaging of meningeal macrophages reveals niche-specific dynamics and aberrant responses to brain hyperexcitability

dlevy1@bidmc.harvard.edu (Anna Gutterman) — Wed, 13 May 2026 00:00:00 +0000

The meninges, which envelop and protect the brain, host a dense network of resident macrophages with diverse roles in regulating homeostasis and neuroinflammation. Despite their importance, we have a limited understanding of their behavior in vivo. Many dynamic cellular functions of macrophages involve intracellular Ca²⁺ signaling. However, virtually nothing is known about the spatiotemporal Ca²⁺ dynamics of meningeal macrophages in vivo. We developed a chronic intravital two-photon imaging approach and related computational analysis tools to interrogate meningeal macrophage Ca²⁺ dynamics, at subcellular resolution, in a novel Pf4-Cre:Ai162 conditional GCaMP6s reporter mouse model. Using imaging in awake mice, we characterized Ca²⁺ activity in meningeal macrophages at steady state and in response to cortical spreading depolarization (CSD), an aberrant pro-inflammatory brain hyperexcitability event implicated in migraine, traumatic brain injury, and stroke. In homeostatic meninges, macrophages in the dural perivascular niche exhibited several Ca²⁺ dynamic features, including event duration and signal frequency spectrum, distinct from those localized to the interstitial, non-perivascular niche. Simultaneous tracking of macrophage Ca²⁺ dynamics and local vasomotion revealed a subset of dural perivascular macrophages whose activity was coupled to locomotion-driven diameter fluctuations of their associated vessels. Most perivascular and non-perivascular meningeal macrophages displayed propagating intracellular Ca²⁺ activity and synchronized intercellular Ca²⁺ elevations, potentially driven by extrinsic factors. In response to CSD, the majority of perivascular and non-perivascular meningeal macrophages showed a persistent decrease in Ca²⁺ activity, while a smaller subset displayed Ca²⁺ elevations. Mechanistically, calcitonin gene-related peptide receptor signaling mediated the increase but not the decrease in CSD-mediated Ca²⁺ signaling. Collectively, our results highlight a previously unknown diversity of Ca²⁺ dynamics in meningeal macrophages at steady state and in response to an aberrant brain hyperexcitability event linked to neuroinflammation.

The long non-coding RNA Dreg1 is required for optimal ILC2 development

ajith.vasanthakumar@petermac.org (Adelynn Tang) — Wed, 13 May 2026 00:00:00 +0000

Gata3 is an essential transcription factor for the development of several distinct immune cell lineages such as T cells, natural killer (NK) cells, and innate lymphoid cells (ILCs). As such, the levels and timing of Gata3 expression are critical for directing lineage fate decisions. The Gata3 locus has a complex and dynamic distal regulatory enhancer landscape. Recently, we identified a non-coding RNA, Dreg1, located immediately upstream of the classic +280 kb T/NK cell enhancer (Tce1). To test its function, we excised the Dreg1 locus in mice and observed a selective reduction of group 2 ILCs (ILC2) across multiple tissues, but mature T, NK, and other ILC lineages remained unchanged. In bone marrow, common innate lymphoid cell progenitors (ILCPs) increased while ILC2 progenitors (ILC2P) decreased, with a modest reduction of Gata3 in upstream progenitors consistent with an early developmental bottleneck. Chromatin profiling showed the Dreg1 locus is accessible in early lymphoid progenitors and became decorated with H3K27ac in ILCP in a Tcf1-dependent manner. Furthermore, Tcf1-deficient cells did not express Dreg1 and showed alterations in the epigenetic landscape of the Dreg1 locus. Finally, we discovered that potential homologues of Dreg1 harboured in a syntenic enhancer of GATA3 are also highly expressed in human ILC2. Taken together, we conclude that Dreg1 is a Tcf1-dependent non-coding RNA critical for fine tuning the high level of Gata3 required for the optimal development of the ILC2 lineage.

HIV-1 envelope glycoprotein modulates CXCR4 clustering and dynamics on the T cell membrane

mmellado@cnb.csic.es (Adriana Quijada-Freire) — Tue, 12 May 2026 00:00:00 +0000

HIV-1 entry into susceptible cells requires the dynamic interaction of its envelope (Env) glycoprotein with the host cell receptor CD4 and a co-receptor, either CCR5 or CXCR4. While the core molecular mechanisms driving Env-receptor interactions and subsequent membrane fusion are well characterized, the precise nanoscale spatial reorganization of these co-receptors at the viral binding site remains poorly defined. In this study, we employed single-particle tracking total internal reflection fluorescence (SPT-TIRF) microscopy to quantitatively analyze nanoscale organizational changes of CXCR4 on the surface of human CD4⁺ T cells following binding by X4-tropic HIV-1. Our data reveal that both recombinant X4-gp120 and virus-like particles expressing physiological levels of X4 Env proteins (gp120 and gp41) promote CXCR4 clustering, a phenomenon linked to cell infection. Furthermore, these ligands induced oligomerization of CXCR4^R334X, a naturally occurring mutant associated with WHIM syndrome that supports HIV-1 infection, but fails to oligomerize in response to CXCL12. Our findings establish a link between CXCR4 clustering and HIV-1 infection, enhancing our understanding of the initial events in viral attachment and entry. These results further suggest that HIV-1 depends on a specific spatial arrangement of co-receptors, distinct from that induced by their natural chemokine ligands, highlighting the critical role of cell-surface receptor spatial organization in dictating cellular function.

B cell expression of an enzymatic intermediary in ether lipid biosynthesis promotes antibody responses and germinal center size

sung.hoon.cho@emory.edu (Clay F Semenkovich) — Mon, 27 Apr 2026 00:00:00 +0000

The qualities of antibody (Ab) responses provided by B lymphocytes and their plasma cell (PC) descendants are crucial facets of responses to vaccines and microbes. Metabolic processes and products regulate aspects of B cell proliferation and differentiation into germinal center (GC) and PC states along with Ab diversification. However, there is little information about lymphoid-cell-intrinsic functions of enzymes that mediate ether lipid biosynthesis. Imaging mass spectrometry (IMS) results had indicated that concentrations of a number of these phospholipids were substantially enhanced in GC compared to the background average in spleens, but it was unclear if biosynthesis in B cells was a basis for this finding, or whether cell-intrinsic biosynthesis contributes to B cell physiology or Ab responses. Ether lipid biosynthesis can involve the enzyme PexRAP, encoded by the Dhrs7b gene. Using IMS and immunization experiments in mouse models with inducible Dhrs7b loss of function, we now show that B-lineage-intrinsic expression of PexRAP promotes the magnitude and affinity maturation of a serological response. Moreover, the data revealed a Dhrs7b-dependent increase in ether phospholipids in primary follicles with a more prominent increase in GC. Mechanistically, PexRAP impacted B cell proliferation via enhanced survival associated with controlling levels of ROS and membrane peroxidation. These findings reveal a vital role of this peroxisomal enzyme in B cell homeostasis and the physiology of humoral immunity.

Clathrin-independent endocytosis and retrograde transport in cancer cells tune immune synapse organization and CD8 T cell response

henri-francois.renard@unamur.be (Alix Buridant) — Wed, 22 Apr 2026 00:00:00 +0000

Endophilin A3-mediated clathrin-independent endocytosis (EndoA3-mediated CIE) contributes to the internalization of immunoglobulin-like proteins, including key immune synapse components. Here, we identify ICAM1 as a novel EndoA3-dependent cargo, alongside ALCAM. We demonstrate that both proteins subsequently follow retromer-dependent retrograde transport to the trans-Golgi network (TGN) in cancer cells. From there, we propose that they undergo polarized redistribution to the plasma membrane, where they contribute to immune synapse formation between cancer cells and cytotoxic CD8 T cells. Disruption of EndoA3 or retromer components significantly affects the response of autologous cytotoxic CD8 T cells, as evidenced by reduced cytokine production and secretion, but increased lytic activity, while proliferation and later activation marker expression remain intact. This is accompanied by diminished ICAM1 density at the immune synapse, where we observe it arriving via polarized vesicular transport, indicating altered synapse organization. Indeed, cancer cells lacking EndoA3-mediated CIE or retromer form enlarged immune synapses that fail to sustain full T cell cytokine secretion, suggesting a compensatory attempt by T cells to overcome the defective synapse, while likely promoting more transient contacts that potentially favor serial killing. Together, these findings reveal that EndoA3-mediated CIE and retrograde transport act in concert in cancer cells to relocate immune synapse components via the Golgi, thereby fine-tuning the balance between cytotoxic T cell cytokine secretion and lytic activity. These insights contribute to a better understanding of the mechanisms governing immune synapse formation and organization, providing a necessary foundation for the long-term identification of new strategies to enhance T cell–mediated anti-tumor immunity.

HEB collaborates with TCR signaling to upregulate Id3 and enable γδT17 cell maturation in the fetal thymus

manderso@sri.utoronto.ca (Cornelis Murre) — Wed, 22 Apr 2026 00:00:00 +0000

T cells expressing the γδ T cell receptor (TCR) develop in a stepwise process initiating at the αβ/γδ T cell branch point, followed by maturation and acquisition of effector functions, including the ability to produce interleukin-17 (IL-17) as γδT17 cells. Previous studies linked TCR signal strength and fate choices to the transcriptional regulator HEB (Tcf12) and its antagonist, Id3, but how these factors regulate different stages of γδ T cell development has not been determined. We found that immature fetal γδTCR⁺ cells from conditional Tcf12 knockout (HEB cKO) mice were defective in activating the γδT17 program at an early stage, whereas Id3-deficient (Id3-KO) mice displayed a partial block in γδT17 maturation and a defect in IL-17 production. We also found that HEB cKO mice failed to upregulate Id3 during γδT17 development, whereas HEB overexpression elevated the levels of Id3 in collaboration with TCR signaling. Moreover, Egr2 and HEB were bound to several of the same regulatory sites on the Id3 gene locus in the context of early T cell development. Therefore, our findings reveal an interlinked sequence of events during which HEB and TCR signaling synergize to upregulate Id3, which enables maturation and acquisition of the γδT17 effector program.

Taking the biology seriously makes models better

a.gil@ucl.ac.uk (Andreas Tiffeau-Mayer) — Mon, 20 Apr 2026 00:00:00 +0000

A new biologically-informed training paradigm enables protein language models to predict affinity maturation trajectories for antibodies.

Heat shock factor regulation of antimicrobial peptides expression suggests a conserved defense mechanism induced by febrile temperature in arthropods

lsshjg@mail.sysu.edu.cn (Bang Xiao) — Thu, 16 Apr 2026 00:00:00 +0000

Temperature is a critical factor influencing the outbreak and progression of viral diseases in organisms. Febrile temperatures have been shown to enhance immune competence and reduce viral replication in various species. However, the underlying mechanisms remain largely unknown. In this study, we investigate the molecular mechanisms by which elevated temperatures confer resistance to viral infections, focusing on the role of heat shock factor 1 (HSF1) in regulating antimicrobial effectors rather than the traditional target genes molecular chaperones. Using shrimp Litopenaeus vannamei as a model, we demonstrate that febrile temperatures induce HSF1, which in turn upregulates antimicrobial peptides (AMPs) that target viral envelope proteins and inhibit viral replication. Importantly, this is the first to show that HSF1 directly binds to the heat shock element (HSE) motifs of AMPs both in shrimp and Drosophila S2 cells, suggesting this may be a conserved regulatory mechanism in arthropods. Additionally, our findings highlight the role of HSF1 beyond the classical heat shock response, revealing its critical function in modulating innate immunity. These insights provide new avenues for managing viral infections in aquaculture and other settings by leveraging environmental temperature control.

Synaptotagmin 1 and Synaptotagmin 7 promote MR1-mediated presentation of Mycobacterium tuberculosis antigens

karamooz@ohsu.edu (Andrew J Olive) — Tue, 14 Apr 2026 00:00:00 +0000

Mycobacterium tuberculosis (Mtb) is an intracellular pathogen that can be sensed by T cells, which are essential for the control of infection. In comparison to viral infections, Mtb antigens are relatively limited and hence, challenging to sample. Specialized antigen presentation pathways enable the presentation of such scarce antigens to CD8⁺ T cells, which are, thus, uniquely poised to survey intracellular environments. A subset of CD8⁺ T cells prevalent in the airways, known as mucosal-associated invariant T (MAIT) cells, can be activated through the presentation of Mtb antigens via the major histocompatibility complex class I-related protein 1 (MR1) molecule. Prior work demonstrates that endosomal calcium signaling is critical for MR1-mediated presentation of Mtb-derived antigens. Here, we show that the calcium-sensing trafficking proteins Synaptotagmin (Syt) 1 and Syt7 specifically promote MAIT cell activation in response to Mtb-infected cells. In bronchial epithelial cells, Syt1 and Syt7 localize to late endo-lysosomes and MR1 vesicles. Loss of Syt1 and Syt7 results in enlarged MR1 vesicles and an increased number of MR1 vesicles in close proximity to Mtb-containing vacuoles during infection. This study identifies a specialized pathway in which Syt1 and Syt7 facilitate the translocation of MR1 from Mtb-containing vacuoles, potentially to the cell surface for antigen presentation.

Contrasting roles for IKK-regulated inflammatory signalling pathways for development and maintenance of type 1 and adaptive γδ T cells

icarvalho@virtus-rr.com (Benedict Seddon) — Fri, 10 Apr 2026 00:00:00 +0000

The inhibitor of kappa-B kinase (IKK) complex is a critical regulator of cell death and inflammatory signalling in multiple cell types. Phosphorylation of IκB proteins by IKK results in their degradation and consequent activation of NF-κB transcription factors. RIPK1, a critical cell death regulator, is also a direct target of IKK kinase activity, thereby repressing its cell death activity. In αβ T cells, the RIPK1 kinase activity of IKK is critical for normal thymic development while mature αβ T cells require IKK for both activation of NF-κB dependent survival programmes and repression of RIPK1. γδ T cells play a unique and versatile role in host immunity with specific effector functions that enable them to act as early responders in immune defence. The role of IKK-regulated pathways in their development and survival is not known. Here, we dissect the function of IKK and downstream pathways for normal γδ T cell homeostasis. We find that IKK is critical to establish replete γδ T cell populations, but that mechanism varys between different subsets. Type 1 γδ T cells require IKK-dependent NF-κB activation for their generation, while IKK is redundant for development of adaptive γδ T cells. Instead, IKK-dependent NF-κB activation is required for their long-term survival. We also find evidence that IKK repression of RIPK1 is required for survival of peripheral but not thymic γδ T cells. Ablation of CASPASE8 did not rescue γδ T cells in the absence of IKK but rather revealed a potent sensitivity of all γδ subsets to necroptosis, which was rescued by kinase-dead RIPK1. Overall, we reveal critical requirements for IKK-regulated inflammatory pathways by γδ T cells that contrast with those of αβ T cells, and between different subsets, highlighting the complexity of the regulation of these pathways in the adaptive immune system.

Separating selection from mutation in antibody language models

matsen@fredhutch.org (David H Rich) — Tue, 07 Apr 2026 00:00:00 +0000

Antibodies are encoded by nucleotide sequences that are generated by V(D)J recombination and evolve according to mutation and selection processes. Existing antibody language models, however, focus exclusively on antibodies as strings of amino acids and are fitted using standard language modeling objectives such as masked or autoregressive prediction. In this paper, we first show that fitting models using this objective implicitly incorporates nucleotide-level mutation processes as part of the protein language model, which degrades performance when predicting effects of mutations on functional properties of antibodies. To address this limitation, we devise a new framework: a deep amino acid selection model (DASM) that learns the selection effects of amino acid mutations while explicitly factoring out the nucleotide-level mutation process. By fitting selection as a separate term from the mutation process, the DASM exclusively quantifies functional effects: effects that change some aspect of the function of the antibody. This factorization leads to substantially improved performance on standard functional benchmarks. Moreover, our model is an order of magnitude smaller and multiple orders of magnitude faster to evaluate than existing approaches, as well as being readily interpretable.

Nociceptor neurons control pollution-mediated neutrophilic asthma

sebastien.talbot@ki.se (Ajitha Thanabalasuriar) — Fri, 27 Mar 2026 00:00:00 +0000

The immune and sensory nervous systems, having evolved in parallel, communicate through shared receptors and transmitters to maintain homeostasis and respond to both external and internal disruptions. Although neural responses often confer protective benefits, they can also exacerbate inflammation during allergic reactions such as asthma. In our study, we modeled pollution-exacerbated asthma by exposing mice to ambient PM_2.5 particles alongside ovalbumin. Compared to exposure to ovalbumin alone, this co-exposure significantly increased the numbers of neutrophils and γδ T cells in bronchoalveolar lavage fluid and lung tissue, respectively. We found that silencing nociceptor neurons at the peak of inflammation using intranasal QX-314 or ablating Trpv1-expressing neurons reduced lung neutrophil accumulation. Live in vivo intravital imaging confirmed that neuronal ablation reduced neutrophil numbers and increased their net displacement capacity. In neurons isolated from mice with pollution-exacerbated asthma, the chemical-sensing TRPA1 channel exhibited heightened sensitivity to its cognate ligand. Elevated levels of artemin were detected in the bronchoalveolar lavage fluid of pollution-exposed mice but returned to baseline in mice with ablated nociceptor neurons. Alveolar macrophages expressing the pollution-sensing aryl hydrocarbon receptor were identified as a putative source of artemin following exposure to PM_2.5. This molecule enhanced TRPA1 responsiveness and, in turn, drove nociceptor-mediated neutrophil recruitment, revealing a novel mechanism by which lung-innervating neurons respond to air pollution in the context of allergy. Overall, our findings suggest that targeting artemin-driven pathways could provide a therapeutic strategy for controlling neutrophilic airway inflammation in asthma, a clinical condition typically refractory to treatment.