European Journal of Immunology最新文献

Antiphospholipid antibodies (aPL) are drivers of inflammation and thrombosis in antiphospholipid syndrome (APS). However, the molecular mechanisms underlying infection-induced exacerbation of APS remain incompletely understood. To identify novel pathways contributing to the pro-inflammatory and pro-coagulant activation of monocytes in APS, we screened fourteen Toll-like receptor (TLR) ligands for their ability to induce tissue factor (TF) expression in a monocyte-like cell line (THP-1). Among these, Pam3CSK4, a synthetic TLR1/2 ligand, emerged as a potent inducer of TF in the presence of aPL. Subsequent experiments revealed that Pam3CSK4 synergized with aPL to amplify both TF expression and IL-1β secretion. This synergistic effect was mediated via NF-κB signaling and required activation of the NLRP3 inflammasome. aPL priming promoted ATP release, providing the second signal for NLRP3 activation. Inhibition of NLRP3 markedly reduced Pam3CSK4-induced TF expression, suggesting a critical role for inflammasome signaling in monocyte procoagulant responses. These in vitro findings were confirmed in a mouse model of APS, supporting the pathogenic relevance of the TLR1/2–NLRP3 axis in vivo. Taken together, our results validate the “second hit” paradigm in APS and suggest a novel TLR1/2–NLRP3 axis as a key mediator of infection-driven inflammatory and thrombotic responses in aPL-primed monocytes.

Type 1 diabetes (T1D) results from T cell-mediated destruction of insulin-producing pancreatic beta-cells. Recently, the immune-provoking role of stress-related neoantigens has become evident. Neoantigens unlikely contribute to central tolerance and therefore hold strong immunogenic potential, but their role in peripheral immune regulation is unknown. Here, we sought proof of concept that Tregs can be generated against islet neoantigen INS-DRiP that results from stress-induced ribosomal misreads of insulin mRNA. Tregs were induced from naïve CD4 T cells isolated from a healthy donor and co-cultured with monocyte-derived tolerogenic DCs either pulsed with neoantigen INS-DRiP or native autoantigen (proinsulin-peptide C19A3) that can induce Tregs in T1D patients. Their phenotypes, cytokine profiles and suppressive capacity were compared. Tregs induced against neoantigen completely inhibited proliferation of naïve T cells upon cognate antigen-pulsed DC stimulation, which was indistinguishable from Tregs induced against C19A3. Phenotype and cytokine profiling showed co-clustering of native autoantigen- and neoantigen-specific Tregs, and distinction from T cells generated with antigen-pulsed proinflammatory instead of tolerogenic DCs. Naïve T cells exist against islet neoantigen that can be primed to become Tregs despite the high immunogenic potential of neoantigen. Induction of immune regulation to neoantigens may be useful as immune intervention or prevention of T1D.

Discovered in the late 19th century as a heat-sensitive plasma factor called “alexin”, complement was first identified for its ability to work with antibodies to destroy microorganisms. Over the past two centuries, research advances have firmly established the complement system as a fundamental component of the immune system, with broader roles in immune surveillance, inflammation, and clearing immune complexes and apoptotic debris, while also bridging innate and adaptive immunity. Due to complement playing a central role in modulating biological processes on a system-wide scale, dysregulation or excessive activation can drive harmful inflammation and self-tissue damage. Despite some initial safety concerns and biological complexity, therapeutic targeting of the complement system has, over the past decade, emerged as a key strategy for controlling disorders in which its unregulated activation becomes pathogenic. However, inhibition of complement, particularly at the level of C3 or C5, predisposes patients to infections, most notably by encapsulated bacteria. These include a markedly increased risk of invasive infections caused by Neisseria meningitidis, as well as susceptibility to Streptococcus pneumoniae, Haemophilus influenzae, and other opportunistic viral and fungal pathogens. In this review, we aim to describe the infection risks associated with therapeutic complement inhibition and outline emerging approaches to mitigate their complications. These include optimised vaccination protocols, antimicrobial prophylaxis, patient education, and surveillance programs, as well as next-generation approaches such as pathway-selective inhibitors, personalised risk stratification, and adjunctive immune support. Enhancing these protective measures will be vital to optimising the therapeutic benefit of complement inhibition while reducing infectious morbidity and mortality.

Removal of Fc-fragments from human IgG or Fc-fused proteins. (1) IgG or Fc-fusion proteins are incubated with IdeS-Fc; (2) Fc fragments are retained using protein G agarose beads; and (3) the F(ab’)₂ fragments or Fc-free proteins are collected by centrifugation in the original buffer without IdeS contamination.

Our cover features images related to flow cytometry techniques widely used for analysis of function and phenotypes of major human and murine immune cell subsets, superimposed on a multidimensional immune cell population scatter plot. These images are taken from the third edition of EJI's Flow Cytometry Guidelines by Cossarizza et al., a comprehensive resource prepared by flow cytometry and immunology research experts from around the world.

The possibility of enhancing T cell function by deleting specific genes represents a long-sought goal in preclinical studies and ultimately for clinical applications. Using CRISPR/Cas9 genome editing, we report that, in human cytotoxic CD8 T cell clones, the cell cycle checkpoint gene CDKN2A, encoding p16^INK4A, plays a nonredundant role in controlling T cell receptor (TCR)-dependent and independent cell expansion. Deletion of CDKN2A dramatically enhanced antigen-driven and homeostatic proliferation, while preserving effector functions. In contrast, the deletion of other cell cycle inhibitors (CDKN1B, CDKN2C, and CDKN2D), alone or in combination, had no impact on T cell proliferation. We also report that mediator complex subunit 12 (MED12) and the E3 ubiquitin ligase CBL-B deletions did not affect proliferative capacity of CD8 T cell clones. Interestingly, deletion of the negative regulator of Ras signaling, RASA2, increased antigen sensitivity and cytotoxic activity, while not improving in vitro expansion. Collectively, these findings reveal a unique and critical nonredundant role for p16^INK4A in regulating CD8 T cells. Deletion of CDKN2A offers a promising strategy to enhance CD8 T cell expansion ex vivo, thereby improving TCR discovery pipelines and, potentially, therapeutic applications.

The continuous evolution of SARS-CoV-2 raises concerns about immune escape from preexisting immunity. The monovalent JN.1adapted mRNA vaccine was developed to better match circulating variants, yet data on its ability to induce and broaden humoral and cellular immunity in individuals with or without prior infection remain limited. We recruited 37 immunocompetent adults before and two weeks after JN.1 vaccination to assess vaccine-induced immunity. Spike-specific CD4 and CD8 T cells were quantified following stimulation with spike-derived peptides from the parental strain, XBB.1.5, and JN.1, and their CTLA-4 expression and cytokine profiles were analyzed by flow cytometry. Spike-specific IgG and neutralizing activity against authentic parental, XBB.1.5, JN.1, and KP.3.1.1 isolates were also measured. JN.1 vaccination significantly increased spike-specific CD4⁺ and CD8⁺ T-cell frequencies with comparable cytokine profiles across variants and enhanced CTLA-4 expression. IgG levels and neutralizing titers rose markedly, with the strongest relative increases against Omicron lineage variants. Prior infection was associated with higher neutralizing titers but did not influence T-cell responses. Influenza vaccine co-administration had no adverse effect on JN.1 immunogenicity. These findings indicate that hybrid immunity enhances antibody-mediated protection, while robust, cross-reactive T-cell responses may contribute to sustained protection against severe disease irrespective of infection history.

Traumatic brain injury (TBI) is increasingly recognized not only as an acute mechanical insult but as a trigger of sustained neuroimmune activation that contributes to chronic neurodegeneration. The complement system has emerged as a central mediator linking acute injury to progressive neuroinflammatory pathology. Following TBI, complement is rapidly activated through classical, lectin, and alternative pathways, converging at C3 and generating downstream effector molecules, including opsonins, anaphylatoxins, and the membrane-attack complex. These mediators amplify inflammation, promote cytotoxic signaling, and exacerbate acute neuronal injury while sustaining chronic microglial and astrocytic activation. In the subacute and chronic phases, complement-dependent opsonization drives maladaptive synaptic pruning, leading to progressive loss of synaptic density and cognitive impairment. Complement activation also contributes to circuit dysfunction and impairs endogenous repair processes by suppressing neurogenesis and neuroblast migration. Preclinical studies consistently identify upstream complement activation, particularly at the level of C3, as a key driver of chronic pathological processes. Consistent with this concept, targeted complement inhibition preserves synaptic integrity and improves functional outcomes. These findings position complement as a promising therapeutic target and support a paradigm shift toward targeting chronic neuroinflammation to prevent long-term neurological sequelae after TBI.