Abstract
Epstein-Barr virus-induced gene 3(EBI3) is conventionally viewed as a subunit of IL-27 and IL-35, yet the function of uncomplexed “free” EBI3 is unknown. We show that free EBI3 is an autonomous immunosuppressive cytokine that acts via a gp130/WSX-1/STAT3 axis and epigenetic reprogramming. A free-EBI3-specific sandwich ELISA revealed 23.3 ± 2.2 ng/mL in healthy human sera and equivalent levels in mice; no cross-reactivity with IL-27/IL-35 was observed. Serum free EBI3 was reduced in rheumatoid arthritis(RA; 12.4 ± 1.4 ng/mL) and multiple sclerosis (MS; 14.6 ± 1.4 ng/mL; both p< 0.001) and inversely correlated with disease activity(RA-DAS28-ESR r=-0.67; MS-EDSS r=-0.61). Baseline<15 ng/mL predicted higher flare risk(RA HR = 2.8;MS HR = 3.2;p<0.01). Recombinant free EBI3 activated STAT3 exclusively(EC50≈16 nM), suppressed T-cell proliferation (-40%),IFN-y(-45%) and IL-17(-60%),and drove M2 macrophage polarization (+2.7-fold;p<0.001).Epigenetically,it reduced H3K4me3 at Ifng/Il4 promoters, induced Il10/Tgfb hypomethylation(-35%/-28%), and remodeled 1,021 chromatin-accessible STAT3/NF-kB sites. EBI3-/- mice developed spontaneous colitis and severe EAE; daily free EBI3(1 mg/kg) reversed pathology, whereas IL-27/IL-35 did not. Tissue-targeted delivery(liposomes or nanoparticles) outperformed systemic therapy. Ex-vivo free EBI3 normalized RA/MS patient PBMCs(proliferation-50%; IL-17-52%; p< 0.001). Thus, free EBI3 is a distinct cytokine whose gp130/WSX-1 axis constitutes a biomarker and therapeutic target for inflammatory diseases.
1 Introduction
Epstein-Barr virus-induced gene 3 (EBI3), a member of the IL-6/IL-12 cytokine family, has long been defined by its role as a shared subunit of two pleiotropic cytokines: IL-27 (EBI3 + p28) and IL-35 (EBI3 + p35) (–). IL-27 balances pro- and anti-inflammatory responses via gp130/WSX-1-dependent activation of STAT1 and STAT3 (–), while IL-35 mediates potent immunosuppression through gp130/gp130 homodimers and STAT5 activation (, ). However, this binary model fails to explain emerging observations: EBI3 mRNA and protein are detected in tissues and biofluids (e.g., synovial fluid of RA patients, BALF of asthmatics) where p28 and p35 expression is undetectable (–), suggesting the existence of free EBI3 with autonomous biological function.
A critical barrier to investigating free EBI3 has been the lack of specific detection tools—conventional ELISAs measure total EBI3 (free + complexed with p28/p35), precluding definitive distinction between monomeric and heterodimeric forms. Additionally, the receptor-signaling pathway for free EBI3 remains unknown: while IL-27 and IL-35 use gp130 as a common receptor subunit, free EBI3’s ability to engage these receptors (or novel ones) and activate downstream pathways has not been tested. Epigenetic mechanisms, which play central roles in immune cell polarization and tolerance (–), have also not been linked to EBI3 activity—leaving open whether free EBI3 modulates chromatin state to enforce immunosuppression.
Translational gaps further persist: if free EBI3 is an immunosuppressive mediator, its deficiency could contribute to inflammatory diseases, and its restoration could offer therapeutic benefit. However, no studies have correlated free EBI3 levels with human disease activity or tested free EBI3 as a therapeutic agent in preclinical models of autoimmunity, allergy, or transplant rejection.
To address these gaps, we hypothesized that free EBI3 acts as an autonomous immunosuppressive cytokine via a gp130/WSX-1/STAT3 axis, inducing epigenetic reprogramming of immune genes to maintain tolerance. In this study, we: (1) developed a free EBI3-specific ELISA; (2) defined its receptor-signaling and epigenetic mechanisms using complementary genetic, pharmacologic, and omics approaches; (3) validated its in vivo function in EBI3-/- mice with targeted delivery; and (4) linked its deficiency to human inflammatory diseases. Our findings establish free EBI3 as a novel tolerance checkpoint with therapeutic potential.
2 Materials and methods
2.1 Free EBI3-specific ELISA development
Monoclonal antibodies (mAbs) against EBI3 were generated by immunizing BALB/c mice with a synthetic EBI3 peptide (amino acids 120–150; Genscript, HPLC purity >95%). The epitope was predicted to be masked in IL-27/IL-35 via AlphaFold2 modeling. Hybridomas were screened via ELISA for reactivity to free EBI3 but not IL-27/IL-35.
Sandwich ELISA protocol: Capture mAb (clone 1E3, IgG2a) was coated overnight at 4 °C (2 μg/mL in 0.1 M carbonate buffer, pH 9.6). Samples/standards were incubated for 2 h at 37 °C, followed by detection mAb (clone 3G7, IgG1, biotin-conjugated; 1 μg/mL) and streptavidin-HRP (Thermo Fisher 21130, 1:2000 dilution). TMB substrate (Thermo Fisher 34028) was added for 15 min at RT, and the reaction was stopped with 2 M H2SO4. Absorbance was read at 450 nm (reference wavelength 650 nm) using a microplate reader (BioTek Synergy H1).
Assay validation parameters:
Linearity: R² >0.99 over 0.08–20 ng/mL.
Precision: Intra-assay CV <5%, inter-assay CV <8% (n=5 replicates per concentration).
Specificity: No cross-reactivity with IL-27/IL-35 (up to 100 ng/mL), IL-6 (R&D 206-IL), IL-12 (R&D 219-IL), or TNF-α (R&D 210-TA).
2.2 In vitro cell functional assays
Naïve CD4+ T cells were labeled with 5 μM CFSE (Thermo Fisher C34554) for 15 min at 37 °C, then quenched with 5 volumes of cold RPMI-1640 + 10% FBS. Cells (1×105/well) were seeded in 96-well plates pre-coated with anti-CD3 (5 μg/mL, BioLegend 100314) and stimulated with soluble anti-CD28 (2 μg/mL, BioLegend 102116) in the presence/absence of free EBI3 (0.1–20 nM). After 72 h, proliferation was analyzed via flow cytometry (BD FACSCymphony™ A5) by measuring CFSE dilution (excitation 488 nm, emission 525 nm).
Cytokine levels in cell supernatants were quantified using the Luminex® Human/Mouse Cytokine Magnetic Bead Panel (Millipore HCYTOMAG-60K/MCTOMAG-70K) on a Luminex 200 analyzer. Data were normalized to untreated controls (set to 100%).
2.3 Free EBI3 delivery
Lung-targeted liposomes: Free EBI3 was encapsulated in liposomes composed of 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC, Avanti 850365) and cholesterol (Sigma C8667) at a 1:1 molar ratio, with PEG-2000-conjugated anti-ICAM-1 antibody (R&D MAB2179, 5 μg/mg liposome) for targeting. Liposomes were prepared via thin-film hydration followed by extrusion (100 nm membrane, Avanti). Size (100–150 nm) and zeta potential (-15 ± 3 mV) were measured via dynamic light scattering (DLS, Malvern Zetasizer Nano-ZS). Encapsulation efficiency (85%) was determined via HPLC (Agilent 1260).
Gut-targeted nanoparticles: Free EBI3 was loaded into chitosan nanoparticles (low molecular weight, 75–85% deacetylation, Sigma 448869) coated with Eudragit® S100 (Sigma 41160, pH-sensitive polymer that dissolves at pH>7). Nanoparticles were prepared via ionic gelation with tripolyphosphate (TPP, Sigma 79592). Size (100–150 nm) and drug loading (10%) were validated via DLS and UV-Vis spectroscopy (280 nm).
2.4 Statistical analysis
Data were analyzed using R v4.5.1. Continuous variables: Presented as mean ± SD (parametric) or median (IQR) (non-parametric). Two-group comparisons: Unpaired Student’s t-test (parametric) or Mann-Whitney U test (non-parametric). ≥3-group comparisons: One-way ANOVA with Tukey’s post hoc test (parametric) or Kruskal-Wallis with Dunn’s post hoc test (non-parametric). Correlations: Pearson’s (parametric) or Spearman’s (non-parametric) correlation coefficient. Survival analysis: Kaplan-Meier curves with log-rank test (RA flares, MS relapses). Sample sizes were determined via power analysis (G*Power 3.1): n=6 per in vivo group (detects 30% difference in clinical scores, 80% power, α=0.05); n=10 per ex vivo group (detects 25% difference in cytokine levels, 80% power, α=0.05). Significance was defined as p<0.05 (*p<0.05, **p<0.01, ***p<0.001, ****p<0.0001).
2.5 Additional methods in supplemental materials
Supplementary Table 1, reagents, cell culture, macrophage polarization, dendritic cell maturation, signal pathway analysis, epigenetic analysis, DNA methylation analysis, ATAC-seq, animal models and clinical studies.
3 Results
3.1 Characterization and clinical relevance of free EBI3
To determine the physiological relevance of monomeric EBI3, we first validated the purity and biochemical properties of recombinant free EBI3. SDS-PAGE and LC-MS confirmed>95% purity and correct sequence coverage(Supplementary Figure 1). Analysis of human and mouse cohorts revealed that free EBI3 levels are significantly reduced in serum and tissues during inflammatory states, strongly associating with disease activity(Figure 1). Specifically, patients with rheumatoid arthritis (RA) and multiple sclerosis (MS) exhibited markedly lower serum free EBI3 concentrations compared to healthy controls, consistent with the inverse correlation between free EBI3 levels and clinical disease scores (RA-DAS28-ESR r = -0.67; MS-EDSS r = -0.61). This suggests that free EBI3, independent of IL-27 or IL-35 complexes, may play a distinct role in immune homeostasis.
Figure 1
3.2 Free EBI3 signals via the gp130/WSX-1 heterodimeric receptor complex
We investigated the molecular mechanism of EBI3 signaling by identifying its receptor partners. Surface plasmon resonance (SPR) experiments were performed on a Biacore T200 instrument (Cytiva) at 25 °C. Recombinant gp130-Fc or WSX-1-Fc (R&D Systems) was immobilized on a CM5 sensor chip using standard amine-coupling chemistry (~800–1,200 response units). Free EBI3 (0.1–100 nM) was injected over the chip surface at a flow rate of 30 μL/min in HBS-EP+ buffer (10 mM HEPES, pH 7.4, 150 mM NaCl, 3 mM EDTA, 0.05% surfactant P20). Actual experimental runs were conducted in triplicate; data were processed with Biacore Evaluation Software using a 1:1 Langmuir binding model to derive kinetic constants (k_a, k_d, K_D). Representative sensorgrams are shown in Figure 2. Using these SPR assays and co-immunoprecipitation(Co-IP), we demonstrated that free EBI3 directly binds to both gp130 and WSX-1 (Figure 2). The specificity of this interaction was validated using neutralizing antibodies against EBI3, p28, and p35, confirming that the observed effects were not due to contaminating IL-27 or IL-35 subunits(Supplementary Figure 2).
Figure 2
To further define the requirement of each receptor subunit, we performed receptor-blocking kinetic experiments. Pre-incubation of CD4+ T cells with a neutralizing anti-gp130 antibody (clone 1B1, 10 μg/mL) reduced free EBI3–induced STAT3 phosphorylation by 78 ± 4% (n = 4, p < 0.001), while an anti-WSX-1 neutralizing antibody (clone 2D3, 10 μg/mL) reduced phosphorylation by 65 ± 5% (n = 4, p < 0.001). Combined blockade of both receptors achieved 92 ± 3% inhibition. Kinetic analysis yielded IC50 values of 3.2 nM for anti-gp130 and 4.8 nM for anti-WSX-1, confirming that both gp130 and WSX-1 are essential for free EBI3 signaling and that their simultaneous engagement drives maximal STAT3 activation.
Binding of free EBI3 to this complex triggered a potent, dose-dependent phosphorylation of STAT3 in CD4+ T cells, with an EC50 of 15.2 nM in mouse cells (Figure 3). To confirm the necessity of these components, we generated CRISPR/Cas9 knockout(KO) Jurkat cell lines for gp130, WSX-1, and Stat3 (Supplementary Figure 3). In these KO models,EBI3-induced signaling was completely abolished, whereas STAT1 and AKT activation remained largely unaffected, demonstrating highly selective signaling via the gp130-STAT3 axis (Figures 4A–J).
Figure 3
Figure 4
3.3 Modulation of T cell proliferation and myeloid phenotypes
Functional assays revealed that free EBI3 is a potent inhibitor of lymphocyte activity. Free EBI3 significantly suppressed the proliferation of both primary CD4+ T cells and Jurkat cells (Figures 4F, H). CFSE dilution assays further visualized this inhibition, showing a marked reduction in the number of dividing cells in EBI3-treated groups (Supplementary Figure 4).
The immunomodulatory reach of EBI3 extended to the innate compartment. In macrophages, EBI3 treatment promoted an M2-like anti-inflammatory profile, while in dendritic cells (DCs), it suppressed LPS-induced maturation and cytokine production (Figure 5). These findings illustrate EBI3 as a broad-spectrum regulator of both innate and adaptive immune responses.
Figure 5
3.4 Epigenetic and chromatin remodeling driven by EBI3
To understand the long-term transcriptional reprogramming caused by EBI3, we performed ATAC-seq to map changes in chromatin accessibility. We identified 1,021 differentially accessible regions (DARs), with 614 regions showing increased accessibility and 407 showing decreased accessibility after EBI3 treatment (Figure 6A). Motif enrichment analysis linked these DARs to STAT3 binding sites and genes involved in immune regulation (Figures 6B–D). Supplemental ATAC-seq data provided high-resolution tracks of regulatory elements for Il10 and Stat3 itself (Supplementary Figures S7–S9).
Figure 6
Further epigenetic characterization showed that EBI3 exposure (15 nM, 24h) increased H3K4me3 and H3K27ac at promoters of anti-inflammatory genes while reducing these marks at pro-inflammatory loci like Ifng and Il17 (Figure 7). Moreover, pyrosequencing revealed that EBI3 induces significant DNA demethylation at the proximal promoters of Il10 and Tgfb (Figures 8A–C). This epigenetic modification was strictly dependent on the presence of gp130 and STAT3, as their deletion precluded EBI3-mediated demethylation (Figures 8D, E).
Figure 7
Figure 8
3.5 Therapeutic efficacy in autoimmune neuroinflammation
The therapeutic potential of free EBI3 was evaluated in the Experimental Autoimmune Encephalomyelitis (EAE) model. While both IL-27 and IL-35 have documented immunosuppressive effects, free EBI3 demonstrated comparable or improved efficacy in reducing clinical scores and preventing weight loss(Figure 9). Notably, direct comparisons of therapeutic potency should be interpreted cautiously, as the pharmacokinetics of monomeric EBI3 and heterodimeric cytokines (IL-27 and IL-35) may differ substantially, potentially affecting in vivo distribution, half-life, and bioavailability.
Figure 9
Flow cytometric analysis of the colon and CNS showed that EBI3 significantly reduced the infiltration of IL-17+ CD4+ T cells(Supplementary Figure 5) and overall CD45+leukocytes(Supplementary Figure 6). Further in vivo analyses confirmed that free EBI3 treatment reduced colonic inflammation associated with the EAE model, showing a marked improvement in tissue architecture compared to vehicle or complexed cytokine controls (Figure 10).
Figure 10
3.6 Systemic impact and long-term protection
Expanding on the EAE results, we characterized the systemic immune environment following EBI3 administration. EBI3 treatment shifted the balance of circulating T cells toward a regulatory phenotype and suppressed the production of Th1/Th17 cytokines in the periphery (Figure 11). Dose-response studies in vivo identified the optimal therapeutic window, showing significant efficacy at low nanomolar concentrations without systemic toxicity (Figure 12; Supplementary Figures 10, S11).
Figure 11
Figure 12
Finally, we examined the durability of EBI3-mediated protection. Mice treated during the induction phase of EAE showed sustained resistance to disease relapse, suggesting the induction of immune memory or long-term epigenetic stability (Figure 13; Supplementary Figure 12). Comparative analyses using EBI3-Fc fusion proteins (to increase half-life) and additional organ-specific histology (liver, lung, and kidney) confirmed the safety and enhanced pharmacological profile of the EBI3-based therapeutic approach (Figure 14; Supplementary Figures 13, S14).
Figure 13
Figure 14
Together, these results establish free EBI3 as a distinct, receptor-specific cytokine that utilizes the gp130/WSX-1/STAT3 axis to epigenetically reprogram immune cells toward a tolerant state, offering a potent therapeutic strategy for autoimmune diseases.
4 Discussion
The discovery of the Epstein-Barr virus-induced gene 3 (EBI3) as a shared subunit for IL-27 and IL-35 established it as a cornerstone of immune regulation. However, the long-standing assumption that EBI3 functions exclusively within these heterodimeric complexes has limited our understanding of its full biological potential. Our study provides definitive evidence that EBI3 exists and functions as a standalone “free” cytokine with potent immunomodulatory properties. By characterizing its signaling through the gp130/WSX-1 receptor complex and its ability to drive stable epigenetic reprogramming, we define a previously unrecognized pathway to immune tolerance that is distinct from the pathways utilized by IL-27 or IL-35. While direct therapeutic comparisons are complicated by differences in pharmacokinetic profiles between monomeric and heterodimeric cytokines, the selective STAT3 activation by free EBI3 offers a potentially advantageous signaling profile.
A significant observation in this work is the specific reduction of free EBI3 levels in inflammatory states, which inversely correlates with disease severity. While many cytokines are upregulated during immune activation, the observed deficiency of free EBI3 in patients with RA and MS suggests that insufficient EBI3 signaling may contribute to loss of immune tolerance. The efficacy of free EBI3 supplementation in our EAE models supports this interpretation, suggesting that restoring EBI3 levels may act as a therapeutic “negative feedback” signal designed to prevent collateral tissue damage. Our results show that free EBI3 treatment effectively reduces both central nervous system and colonic inflammation. The comparison with IL-27 and IL-35 complexes is complicated by differences in pharmacokinetic properties—notably, the monomeric EBI3 has a shorter predicted half-life than the heterodimeric cytokines. Nevertheless, when equivalent molar amounts were administered, free EBI3 showed comparable or improved therapeutic effects, which may be attributed to its selective signaling profile. Specifically, while IL-27 is known to activate both STAT1 and STAT3—potentially promoting pro-inflammatory Th1 responses under certain conditions—free EBI3 exhibits a highly selective bias toward STAT3. This selectivity may explain its robust ability to inhibit T cell proliferation and drive macrophages toward a protective M2-like phenotype without the inflammatory “noise” associated with multimeric cytokine signaling.
A direct comparison of the therapeutic efficacy of free EBI3 versus IL-27 or IL-35 is constrained by differences in their pharmacokinetic profiles. Monomeric EBI3 (approximately 25 kDa) is predicted to have a shorter systemic half-life compared to the heterodimeric complexes (IL-27, approximately 50 kDa; IL-35, approximately 45 kDa), which may affect tissue distribution and clearance rates. Future studies incorporating pharmacokinetic analysis—including measurement of serum half-life, tissue biodistribution, and receptor occupancy—will be essential to rigorously compare the therapeutic potentials of free EBI3 and its heterodimeric counterparts.
The identification of the gp130/WSX-1 heterodimer as the functional receptor for free EBI3 clarifies the molecular architecture of this signaling axis. The high sensitivity of CD4+ T cells to EBI3, evidenced by an EC50 of approximately 15.2 nM, indicates that EBI3 operates within a physiological concentration range typically found in the inflamed microenvironment. Furthermore, our CRISPR/Cas9 knockout studies demonstrate that this signaling is strictly dependent on the gp130-STAT3 pathway. This pathway appears to be the primary engine for the profound chromatin remodeling we observed via ATAC-seq. By identifying over 1,000 differentially accessible regions, we have mapped a specific EBI3-induced “tolerance landscape” characterized by the opening of regulatory elements near genes such as Il10 and Tgfb, and the closing of regions associated with Th1 and Th17 pathogenicity.
It is important to note that free EBI3, IL-27, and IL-35 likely exhibit distinct pharmacokinetic profiles. As a monomer, free EBI3 (~28 kDa) is considerably smaller than the heterodimeric IL-27 (~55 kDa) and IL-35 (~52 kDa), which may result in faster renal clearance, differing tissue penetration, and altered receptor-binding stoichiometry in vivo. Therefore, the observed therapeutic effects in EAE models cannot be attributed solely to intrinsic signaling potency; differences in half-life and biodistribution may also contribute. Future studies incorporating detailed pharmacokinetic analyses will be essential to disentangle these variables and enable rigorous comparisons of monomeric versus heterodimeric cytokine therapies.
Perhaps the most impactful finding of this study is the evidence for EBI3-mediated epigenetic memory. Beyond transient transcriptional changes, EBI3 induces active DNA demethylation at the Il10 and Tgfb promoters and modulates histone marks at key cytokine loci. This transition from a transient response to a stable epigenetic state provides a mechanistic basis for the long-term protection observed in our EAE relapse models. Mice treated with EBI3 maintained reduced clinical scores long after the cessation of treatment, suggesting that EBI3-treated T cells are fundamentally reprogrammed toward a regulatory identity. This “fixed” tolerance is a highly desirable trait for biotherapeutics, as it potentially minimizes the need for chronic, high-dose administration.
From a clinical perspective, the development of EBI3-Fc as a stable therapeutic agent addresses the pharmacological challenges of using monomeric cytokines. Our safety and dose-response data reinforce the viability of this approach, showing potent systemic suppression of autoimmunity without evident organ toxicity. While further research is needed to determine the precise cellular sources of free EBI3 in vivo and its role in human chronic inflammatory diseases, our findings establish a new paradigm for cytokine therapy. By leveraging the specific epigenetic-modifying power of the EBI3-gp130-STAT3 axis, it may be possible to induce durable immune tolerance in patients with refractory autoimmune disorders.
In conclusion, our data redefine EBI3 as an independent cytokine that functions as a master regulator of immune homeostasis. By shifting the focus from heterodimeric complexes to the monomeric form, we have uncovered a potent signaling axis that epigenetically rewires immune cells toward anti-inflammatory functions, offering a promising new direction for the treatment of inflammatory and autoimmune diseases.
Statements
Data availability statement
The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding author/s.
Ethics statement
The studies involving humans were approved by Shenzheng University Human Ethics Committee. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study. The animal study was approved by Shenzheng University Animal Ethics Committee. The study was conducted in accordance with the local legislation and institutional requirements.
Author contributions
BM: Data curation, Investigation, Writing – review & editing. RZ: Data curation, Investigation, Writing – review & editing. YY: Data curation, Investigation, Writing – review & editing. LL: Data curation, Investigation, Writing – review & editing. PZ: Data curation, Investigation, Writing – review & editing. HZ: Data curation, Investigation, Writing – review & editing. GY: Conceptualization, Project administration, Writing – review & editing. PY: Conceptualization, Funding acquisition, Project administration, Supervision, Writing – original draft, Writing – review & editing.
Funding
The author(s) declared that financial support was received for this work and/or its publication. This study was supported by research grants of the National Natural Science Foundation of China (32090052), Science, Technology and Innovation Bureau of Shenzhen Municipality (JCYJ20240813143215019 and JCYJ20250604182535045).
Conflict of interest
The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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The author(s) declared that generative AI was not used in the creation of this manuscript.
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Supplementary material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2026.1858675/full#supplementary-material
Abbreviations
EBI3, Epstein-Barr Virus-Induced Gene 3; ChIP, Chromatin immunoprecipitation; ATAC-seq, Assay for transposase-accessible chromatin with sequencing; DARs, Differentially accessible regions; RA, Rheumatoid arthritis; MS, Multiple sclerosis; EAE, Experimental autoimmune encephalomyelitis; GVHD, Graft-versus-host disease; CFSE, Carboxyfluorescein succinimidyl ester; BMDMs, Bone marrow-derived macrophages; BMDCs, Bone marrow-derived dendritic cells; PBMCs, Peripheral blood mononuclear cells; Tr1, Type 1 regulatory T cells; IFN-γ, Interferon-gamma; TGF-β, Transforming growth factor-beta; DAS28-ESR, Disease activity score 28 with erythrocyte sedimentation rate; EDSS, Expanded Disability Status Scale; HC, Healthy controls; OVA, Ovalbumin; LPS, Lipopolysaccharide; CI, Confidence interval; IQR, Interquartile range; AHR, Airway hyperresponsiveness; BALF, Bronchoalveolar lavage fluid.
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Summary
Keywords
allergic disease, autoimmunity, epigenetics, free EBI3, immune regulation, stat3
Citation
Miao B, Zhang R, Ye Y, Li L, Zheng P, Zheng H, Yang G and Yang P (2026) Free Epstein-Barr virus-induced gene 3 functions as an autonomous immunosuppressive cytokine to maintain immune tolerance. Front. Immunol. 17:1858675. doi: 10.3389/fimmu.2026.1858675
Received
17 April 2026
Revised
11 July 2026
Accepted
14 July 2026
Published
27 July 2026
Volume
17 - 2026
Edited by
Michele Costanzo, Università di Napoli Federico II, Italy
Reviewed by
Ebrahim Mazloomi, Urmia University of Medical Sciences, Iran
Ana Ramon-Vazquez, University College Cork, Ireland
Updates
Copyright
© 2026 Miao, Zhang, Ye, Li, Zheng, Zheng, Yang and Yang.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Gui Yang, guiryang@mailnesia.com; Pingchang Yang, pcy2356@163.com
†These authors have contributed equally to this work
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.