Immunology Letters[JOURNAL]
Sun
200 papers
When immunity multitasks: type 2 pathways power thymus regeneration.
Anderson G
Immunol Lett · 2026 Jun · PMID 41748033 · Publisher ↗
αβT-cells are an essential cellular component of the vertebrate immune system. As the sole site of their production, the thymus represents a key orchestrator of the immune system. Despite this importance, intrathymic T-c...
αβT-cells are an essential cellular component of the vertebrate immune system. As the sole site of their production, the thymus represents a key orchestrator of the immune system. Despite this importance, intrathymic T-cell development is a fragile process, and the detrimental impact of multiple environmental, physiologic and therapeutic factors on thymus function is long known. With work performed over the past few decades, we now have a clearer understanding of the ability of the thymus to fight back against tissue damage, through its capacity for endogenous regeneration. Here, pre-clinical mouse models have been of key importance in revealing the presence of multiple intrathymic signalling pathways that act to rebuild the thymus and restore T-cell production and immunity following damage. Of these reported pathways, my own lab has focussed on identifying and studying an intrathymic network that consists of multiple cellular and molecular regulators of type 2 immune responses. At the recent Croatian Society for Immunology congress, I described our work on the role of this network in thymus regeneration, including IL33, ILC2 and eosinophils. In addition, I also highlighted the work of other laboratories in this area of thymus biology, and summarised similarities in the way type 2 immune components regulate tissue regeneration in both thymic and non-thymic tissues. Overall, from the considerable efforts of many researchers, we are hopefully left with a better understanding of how the immune system regulates tissue repair following damage, including one of the tissues that is of key importance in its own functioning.
High expression of IRF8 in AChR-specific cells regulates the function of B cells.
Zhao W, Yan G, Wei B … +8 more , Zhang Y, Yao X, Wang Z, Wang G, Hou L, Zhong L, Wang J, Mu L
Immunol Lett · 2026 Jun · PMID 41730437 · Publisher ↗
Myasthenia gravis (MG) is a kind of autoimmune disease. Interferon regulatory factor 8 (IRF8) is an interferon common sequence-binding protein. IRF8 is a key factor involved in the development, maturation, and antimicrob...
Myasthenia gravis (MG) is a kind of autoimmune disease. Interferon regulatory factor 8 (IRF8) is an interferon common sequence-binding protein. IRF8 is a key factor involved in the development, maturation, and antimicrobial activity of myeloid cells. Second-generation sequencing of splenocytes at the peak period of disease in experimental autoimmune MG (EAMG) rats and complete Freund's adjuvant (CFA)-treated mice suggested that the expression of IRF8 gene is related to the pathogenesis of EAMG. This study focused on the differential expression of IRF8 in B cell and T cell in EAMG, and the underlying mechanism of the role of IRF8 in the pathogenesis of the disease. We analyzed the gene expression profiles of splenocytes from CFA-treated and EAMG mice. We measured the serum anti-acetylcholine receptor autoantibody titer, IRF8 mRNA and protein level in splenocytes, IRF8 mRNA and protein expression in T and B cells as well as in LPS-stimulated splenocytes, and colocalization of CD45R and IRF8 proteins using confocal microscopy. Finally, we determined the titers of anti-acetylcholine receptor autoantibodies in the supernatants of LPS-stimulated cells. Our findings revealed that the expression of IRF8 in splenocytes increased during the peak period of EAMG, B cells exhibited high IRF8 expression, and that IRF8 expression in B cells was positively correlated with antibody secretion. Taken together, our findings indicate that IRF8 is a potential biomarker for EAMG diagnosis.
Immunometabolites and cancer: the role of 2-hydroxyglutarate, succinate, fumarate and itaconate in tumour development and anti-tumour immunity.
Pfefer T, Bessenyei AH, O'Neill LA
Immunol Lett · 2026 Jun · PMID 41724335 · Publisher ↗
The field of immunometabolism has expanded substantially in recent years, with specific metabolic change becoming a key feature that defines the phenotype of immune cells. In cancer however, metabolic change has been inv...
The field of immunometabolism has expanded substantially in recent years, with specific metabolic change becoming a key feature that defines the phenotype of immune cells. In cancer however, metabolic change has been investigated for much longer, and the exploration of oncometabolites as immunometabolites is increasingly being explored. 2-hydroxyglutarate was one of the first oncometabolites to be implicated in tumourigenesis but it also has immunomodulatory effects, with the D enantiomer suppressing anti-tumour immunity via various processes including inhibition of CD8T cells. Fumarate also acts as an oncometabolite, affecting DNA methylation and DNA repair, but again also having immunomodulatory effects via inhibition of T and B cells, whilst also promoting Type I interferon production in macrophages. Succinate can act as an oncometabolite but also in immunomodulation. It has been shown to have pro-tumour effects, acting via HIF-1α and epigenetic modification and regulating tumour-associated macrophages (TAMs). Succinate can also promote T cell exhaustion whilst expanding cancer-associated fibroblasts. Finally, itaconate has been shown to have pro-tumour effects, by either supporting tumour cell survival or by suppressing anti-tumour immunity. TAMs and myeloid-derived suppressor cells are a source of itaconate, which can inhibit CD8T cell responses and suppress tumour antigen presentation by dendritic cells. Emerging evidence indicates that the targeting of these metabolites holds promise for limiting tumour growth but in addition boosting anti-tumour immunity.
Evaluation of the diagnostic and prognostic role of TSPAN32 in B-cell acute lymphoblastic leukemia.
Scuderi G, Cocomero L, Cavalli E … +2 more , Nicoletti F, Fagone P
Immunol Lett · 2026 Jun · PMID 41713511 · Publisher ↗
B-cell acute lymphoblastic leukemia (B-ALL) is an aggressive hematologic malignancy characterized by the uncontrolled proliferation of immature B-cell precursors. Despite therapeutic advances, outcomes remain poor in adu...
B-cell acute lymphoblastic leukemia (B-ALL) is an aggressive hematologic malignancy characterized by the uncontrolled proliferation of immature B-cell precursors. Despite therapeutic advances, outcomes remain poor in adults and relapsed patients, underscoring the need for novel targets. TSPAN32, a tetraspanin family member, is primarily expressed in hematopoietic tissues and implicated in immune regulation. In this study, we have evaluated the TSPAN32 expression across various B-ALL subtypes and correlated it with clinical data. TSPAN32 expression was significantly reduced in all subtypes compared to healthy bone marrow. Expression was relatively uniform within the B-ALL population, unaffected by differentiation stage. A significant negative correlation between TSPAN32 expression and blast percentage was also observed. Survival analysis revealed that lower TSPAN32 expression correlated with poorer overall survival. Gene expression analysis in sample diverging for the expression of TSPAN32 identified key pathways, including immune modulation and ECM processes, associated to TSPAN32 expression. In conclusion, TSPAN32 emerges as a molecule involved in the biology of B-ALL. Its prognostic value, consistent expression across age groups, and involvement in key signaling pathways highlight its potential as a biomarker for B-ALL.
PD-L1 expression in cervical cancer tissue is strongly associated with the expression of CD73/TGF-β1, the percentage of CD8+/PD-1+ T cells and disease progression.
Ricardo MG, Alberto MG, María HÁ … +8 more , Rosario GR, Benny WS, Jorge HM, Azucena DC, Juan Antonio DR, Vadim PK, Gabriela MC, de Lourdes MM
Immunol Lett · 2026 Aug · PMID 41707877 · Publisher ↗
The PD-1/PD-L1 signaling pathway plays a pivotal role in dampening anti-tumor immune responses. We previously reported that adenosine (Ado) increases the expression of programmed death ligand 1 (PD-L1) in cervical cancer...
The PD-1/PD-L1 signaling pathway plays a pivotal role in dampening anti-tumor immune responses. We previously reported that adenosine (Ado) increases the expression of programmed death ligand 1 (PD-L1) in cervical cancer (CC) cells by inducing TGF-β production. We also showed that supernatants from Ado-treated CC cells increased programmed cell death protein 1 (PD-1) expression in CD8+ T lymphocytes. In this study, we investigated the associations between PD-L1, CD73, and TGF-β expression and the percentage of PD-1-expressing CD8+ T lymphocytes in cervical tissue samples from normal donors (NDs), as well as patients with cervical intraepithelial neoplasia (CIN-I, CIN-II, CIN-III) and cervical cancer (CC). This retrospective observational study analyzed biopsies from untreated patients with CIN-1 (n = 27), CIN-II (n = 25), CIN-III (n = 23), and CC (n = 23), in addition to ND tissue samples (n = 30) as controls. Tissue microarrays (TMAs) were generated in triplicate and stained with anti-PD-L1, anti-CD73, anti-TGF-β1, anti-PD-1, and anti-CD8 monoclonal antibodies. Our results showed that the expression of PD-L1, CD73, and TGF-β1, along with the percentage of CD8+/PD-1 + T cells, increased in cervical tissues, correlating with disease progression. PD-L1 expression positively correlated with both CD73 (r = 0.8274, p < 0.001) and TGF-β1 (r = 0.8535, p < 0.001). Interestingly, the coexpression of PD-L1 and TGF-β1 in cervical tissues from patients with CIN-III and CC markedly increased. Furthermore, the percentage of CD8+ cells positively correlated with PD-1 expression (r = 0.7199, p < 0.01). These findings suggest that the expression of PD-L1 and PD-1 in CC tissues is strongly correlated with the expression of CD73 and TGF-β1. Therefore, the joint analysis of these biomarkers could be highly useful for evaluating disease prognosis and for developing strategies to improve the efficacy of immunotherapy protocols in CC patients treated with immune checkpoint inhibitors (ICIs).
APOE isotype-dependent regulation of IgG and IgA levels against different IAPP epitopes.
Pocevičiūtė D, Roth B, Olofsson A … +2 more , Hansson O, Wennström M
Immunol Lett · 2026 Jun · PMID 41698553 · Publisher ↗
The efficient clearance of IAPP oligomers (IAPPo) by autoantibodies is crucial as increased plasma levels of IAPPo can induce microvascular alterations and Alzheimer's disease (AD)-characteristic amyloid-β deposition in...
The efficient clearance of IAPP oligomers (IAPPo) by autoantibodies is crucial as increased plasma levels of IAPPo can induce microvascular alterations and Alzheimer's disease (AD)-characteristic amyloid-β deposition in the brain. We have recently demonstrated that plasma immunoglobulin (Ig) A levels against IAPPo, but not IgG, are reduced in an Apolipoprotein E (APOE) ε4 allele dose-dependent manner. In this study, we aimed to investigate if this APOE genotype-dependent impact can be explained by differences in IAPP epitope recognition by IgA and IgG. We found that the specificity for IAPP epitopes does not differ between IgG and IgA autoantibodies and that IgG and IgA autoantibodies are directed foremost against the C-terminus of the IAPP. However, IgG autoantibody levels against the N-terminus and midportion of IAPP increased significantly in AD patients with APOE44 compared to controls with APOE33, while the opposite was seen in IgA autoantibody levels. We propose that the IgG and IgA levels against different IAPP epitopes are APOE isotype-dependent, possibly due to differences in cytokine profile between various APOE genotypes or the need for different effector functions of IgG or IgA.
Ferroportin is a candidate regulator of dendritic cell-mediated immune tolerance.
Nam JH, Song MS, Choi SY … +6 more , Noh KE, Kim DH, Jung NC, Lee JH, Song JY, Lim DS
Immunol Lett · 2026 Jun · PMID 41690407 · Publisher ↗
Dendritic cells (DCs) are central regulators of immunity, yet the molecular mechanisms underlying their tolerogenic function remain incompletely defined. In our previous study, ferroportin (FPN) was highly expressed in t...
Dendritic cells (DCs) are central regulators of immunity, yet the molecular mechanisms underlying their tolerogenic function remain incompletely defined. In our previous study, ferroportin (FPN) was highly expressed in tolerogenic DCs (tolDCs), but its impact on their immunological function was unclear. Here, we investigated the role of FPN in the immunomodulatory properties of tolDCs. Compared with mature DCs (mDCs), tolDCs exhibited significantly increased FPN expression, reduced expression of co-stimulatory molecules and pro-inflammatory cytokines, and enhanced differentiation of T helper type 2 cells (Th2) and regulatory T cells (Tregs). Knockdown of FPN in tolDCs diminished Treg differentiation and IL-10 production, indicating that FPN is essential for the tolerogenic phenotype. These findings suggest that FPN affects tolDC-mediated immune modulation and contributes to the establishment of a tolerogenic immune environment, providing new insight into mechanisms of immune tolerance.
Substrate availability and citrate alter TCA cycle metabolism and SLC13A3 in macrophage immune responses.
Woyciechowski L, Willenbockel HF, Cordes T
Immunol Lett · 2026 Jun · PMID 41672351 · Publisher ↗
Cell culture media are commonly formulated to enhance cell growth and often lack the physiological nutrient composition found in human blood plasma. The impact of substrate availability on immune cell metabolism and func...
Cell culture media are commonly formulated to enhance cell growth and often lack the physiological nutrient composition found in human blood plasma. The impact of substrate availability on immune cell metabolism and function remains incompletely understood. Here, we demonstrate that changes in culture medium composition affect mitochondrial metabolic pathways, immune responses, and transport in macrophages. Using mass spectrometry and stable isotope tracing, we identify citrate as a mediator linking extracellular substrate availability to intracellular metabolism. We also observe increased IL-6 secretion and elevated expression of plasma membrane transporter NaDC3 (SLC13A3) under physiological carbon source conditions that are reversed when citrate is excluded from the medium. Our findings demonstrate that extracellular substrate composition influences macrophage immunometabolism and identify citrate as an extracellular signal that modulates immune responses. This work highlights the importance of physiologically relevant nutrient availability in studying and targeting immunometabolic pathways.
Complement involvement in antiphospholipid syndrome.
Hamidi H, Darnige L, Dragon Durey MA
Immunol Lett · 2026 Jun · PMID 41662879 · Publisher ↗
Antiphospholipid syndrome (APS) is an acquired thrombophilia characterized by thrombotic and non-thrombotic (or non-criteria) manifestations, in the context of persistent presence of autoantibodies targeting phospholipid...
Antiphospholipid syndrome (APS) is an acquired thrombophilia characterized by thrombotic and non-thrombotic (or non-criteria) manifestations, in the context of persistent presence of autoantibodies targeting phospholipids and associated proteins. The complement system, which shares common actors with coagulation cascade, is nowadays well established to be implicated in APS pathophysiology in different ways. Animal models using knock out strains or complement blocking therapies have helped to decipher the different complement components implicated in the processes of thrombosis and fetal morbidity. In APS patients, complement activation may be assessed through the detection of activation fragments (C4d, C3a, C5a, sC5b9) in plasma and on blood cells surface (C4d, C3d and C5b9) or on APS-affected tissues such as cardiac valves, vessels walls, kidneys and placentae. APS patients are currently treated to avoid thrombosis recurrence by long-term treatment by vitamin K antagonists but various complement targeting molecules are tested in trials or now available and may be of major interest to treat APS patients. Several cases report described the use of eculizumab, an anti-C5 monoclonal antibody, to treat severe forms of APS (recurrent thrombosis, Catastrophic APS) but these studies are not sufficient and need to be more standardized. C4d measurement may be useful to assess classical and lectin pathways activation, C5a may allow evaluating the C5a/C5aR axis activity whereas, associated with sC5b9, it may also assess the terminal pathway activation but also the therapeutic efficacy of complement blocking molecules. Thus, assessment of good complement biomarkers and their kinetics needs to be done to determine personalized therapeutic options.
Efferocytosis-linked genetic signature predicts rheumatoid arthritis risk and highlights CD300A as a novel target.
Fei H, Mei Y, He J … +4 more , Li Y, Xu R, Liu W, Yu Z
Immunol Lett · 2026 Jun · PMID 41621689 · Publisher ↗
PURPOSE: Rheumatoid arthritis (RA) is a common autoimmune disease causing significant bone lesions. This study aims to explore RA through efferocytosis, identify hub genes, and construct a risk prediction model for clini...
PURPOSE: Rheumatoid arthritis (RA) is a common autoimmune disease causing significant bone lesions. This study aims to explore RA through efferocytosis, identify hub genes, and construct a risk prediction model for clinical management and targeted therapy. METHOD: RA data was obtained from the GEO database. Differential gene expression analysis was performed using R packages. Hub genes were identified via LASSO regression and validated with ROC curves. Functional analysis included constructing PPI, mRNA-miRNA, and transcription factor (TF) networks. Gene modules were analyzed by WGCNA, and immune cell infiltration was assessed using CIBERSORT. CD300A expression was knocked down in macrophages and assessed by immunofluorescence and flow cytometry. In vivo, CD300A was silenced in a CIA mouse model using AAV lentivirus, followed by joint pathology and TUNEL staining. RESULT: Six hub genes were identified: IL1R1, WASL, AIM2, NLRP3, CD24, and CD300A, with coefficients of -1.968, -0.445, 1.367, 0.077, 0.248, and 0.523, respectively. B cells, macrophages, and T cells were significantly correlated with the risk score. Additionally, 30 TFs and 56 candidate miRNAs were identified. Knockdown of CD300A in macrophages enhanced efferocytosis in vitro, while silencing CD300A in vivo reduced joint scores, improved joint pathology, and decreased apoptosis in CIA mice. CONCLUSION: Efferocytosis plays a key role in RA pathogenesis. IL1R1, WASL, AIM2, NLRP3, CD24, and CD300A are significant hub genes for RA prediction, with CD300A being a promising therapeutic target.
Fc receptor-like proteins and their role in B-cell responses and autoimmune diseases.
Haroun C, Kroese FGM, Verstappen GM
Immunol Lett · 2026 Jun · PMID 41617145 · Publisher ↗
Fc receptor-like (FCRL) proteins constitute a receptor family that displays overlapping yet distinct features compared to classical Fc receptors. In a healthy immune system, FCRL proteins play a role in promoting and reg...
Fc receptor-like (FCRL) proteins constitute a receptor family that displays overlapping yet distinct features compared to classical Fc receptors. In a healthy immune system, FCRL proteins play a role in promoting and regulating the immune response through their immunoreceptor tyrosine-based motifs. FCRL proteins are expressed mainly by B cells, suggesting a primary role in B-cell responses. For several autoimmune diseases, studies have shown that particularly FCRL4, which binds to dimeric IgA, and FCRL5, which binds to IgG, may have a role in disease pathology and prognosis. These proteins and their transcripts are often enriched in blood and/or affected tissue of patients with a systemic or organ-specific autoimmune disease like rheumatoid arthritis, Sjögren's disease, systemic lupus erythematous, Graves' disease or myasthenia gravis. The expression of FCRL4 and FCRL5 appears to be disease- and context-specific, and influenced by the tissue microenvironment. Yet, the functions of FCRL proteins are still incompletely understood, and more mechanistic studies are necessary to unravel the contribution of FCRL4 and FCRL5 to pathogenic B-cell responses occurring in autoimmune diseases.
Innate immune activation beyond pathogens: Crosstalk between cellular repair pathways and DAMPs in homeostatic inflammation.
Myers C, Saffarzadeh N, Öberg M … +3 more , Enriquez J, Carlsson J, Härtlova A
Immunol Lett · 2026 Jun · PMID 41617144 · Publisher ↗
Innate immunity has long been viewed as a defense system that evolved to detect and eliminate invading microbes. However, its functions extend beyond pathogen control to the continuous surveillance of cellular integrity....
Innate immunity has long been viewed as a defense system that evolved to detect and eliminate invading microbes. However, its functions extend beyond pathogen control to the continuous surveillance of cellular integrity. Cellular homeostasis relies on repair mechanisms that preserve genome stability, proteostasis, lipid balance, and organelle quality. When these systems fail, endogenous molecules such as nucleic acids, lipids, protein aggregates, and metabolites become mislocalized or modified and act as damage-associated molecular patterns (DAMPs). These signals mark sites of failed repair and activate innate sensors, sustaining inflammation even in the absence of infection. In this minireview, we outline the major classes of DAMPs and show how their accumulation reflects defects in specific repair pathways. We propose that innate immunity and cellular repair are fundamentally interconnected. When repair is intact, inflammation is transient and resolves. When repair fails, inflammation becomes chronic and drives disease.
FOXN1 immunodeficiency detected by TREC-based newborn screening - A challenge of management?
Graafen L, Borkhardt A, Reiß J … +8 more , Soura S, Laws HJ, Uhrberg M, Paulusch S, De Domenico E, Beyer MD, Bennstein SB, Ghosh S
Immunol Lett · 2026 Jun · PMID 41610918 · Publisher ↗
Incomplete genotype-phenotype correlations challenge the management of non-SCID FOXN1 immunodeficiency. We describe the detailed clinical course of three distinct newborns with four novel FOXN1 mutations identified by TR...
Incomplete genotype-phenotype correlations challenge the management of non-SCID FOXN1 immunodeficiency. We describe the detailed clinical course of three distinct newborns with four novel FOXN1 mutations identified by TRECNBS. For comprehensive immune characterization advanced flow cytometry-based immunophenotyping was employed alongside high-resolution single-cell RNA sequencing. In our cohort, we detected heterozygous FOXN1 mutations in P1 (c.1178delG; p.Gly393Alafs*157) and P2 (c.830+1G>T; p.?), and compound heterozygous FOXN1-mutations in P3 (c.1318C>T; p.Gln440* and c.668T>G; p.?). Despite slow and partial recovery from T-cell lymphocytopenia in P3, clinical signs for classical 'nude SCID` were incomplete. Compared to a healthy cord blood control, a distinct B-cell population was identified in the FOXN1-deficient patients expressing immature B-cell markers and lower HLA-II mRNA levels. In summary, our cohort of three newborns with four novel FOXN1 variants highlights heterogeneous immunological courses and broader thymic dysfunction implications in this rare disease. Structured management strategies are essential for those identified by NBS-programs.
Molecular requirements of pathogenic Th2 cell differentiation in allergic airway disease.
Khan M, Fuhrmann V, Cavanagh LL … +1 more , Boucheron N
Immunol Lett · 2026 Jun · PMID 41610917 · Publisher ↗
Th2 cells were originally described as a homogeneous population capable of simultaneously producing interleukin (IL)-4, IL-5, and IL-13, thereby playing a central role in allergic asthma and related conditions. Subsequen...
Th2 cells were originally described as a homogeneous population capable of simultaneously producing interleukin (IL)-4, IL-5, and IL-13, thereby playing a central role in allergic asthma and related conditions. Subsequent studies have revealed substantial heterogeneity within the Th2 lineage, with distinct subpopulations defined by unique surface markers and cytokine profiles. Of particular interest are pathogenic Th2 subsets, referred to as peTh2, Tpath2, or Th2A, that exhibit specialised effector functions and actively drive allergic disease. These pathogenic Th2 (pTh2) cells have been identified across a wide range of human allergic conditions, including conjunctivitis, allergic rhinitis, chronic rhinosinusitis, atopic dermatitis, IgE-mediated food allergy, and eosinophilic gastrointestinal disorders such as eosinophilic esophagitis, underscoring their broad clinical relevance. The molecular requirements for early pTh2 differentiation, as well as the transcriptional networks and epigenetic mechanisms that regulate their maturation, remain incompletely understood. Moreover, pTh2 cells themselves display considerable heterogeneity, circulating in the blood, and residing in secondary lymphoid organs, and peripheral tissues. This review highlights recent advances in the heterogeneity, differentiation, and molecular regulation of pTh2 cells, with a particular focus on their roles in eosinophilic asthma. We review the signalling pathways that drive pTh2 differentiation, their transcriptional and epigenetic regulation, and the diverse subpopulations they encompass. These insights offer a foundation for developing targeted therapies to mitigate type 2-driven allergic inflammation.
Decidual NK cells, extravillous trophoblast and their PD-1/PD-L1 interaction: New insights into recurrent pregnancy loss and placenta accreta spectrum disorders.
Moscheik A, Habets D, Classen-Linke I … +2 more , von Rango U, Severens-Rijvers CAH
Immunol Lett · 2026 Jun · PMID 41580136 · Publisher ↗
OBJECTIVES: Placentation is influenced by decidual Natural Killer (dNK) cells. Defective placentation can lead to recurrent pregnancy loss (RPL) or placenta accreta spectrum (PAS) disorders. Interaction between Programme...
OBJECTIVES: Placentation is influenced by decidual Natural Killer (dNK) cells. Defective placentation can lead to recurrent pregnancy loss (RPL) or placenta accreta spectrum (PAS) disorders. Interaction between Programmed Cell Death Protein 1 (PD-1) on NK cells and Programmed Cell Death 1 Ligand (PD-L1) can alter the cytokine expression and cytotoxic potential of NK cells. This study compares dNK and PD-1 dNK cell number, number of extravillous trophoblast (EVT) and PD-L1 EVTs in two patient groups that experienced either RPL or PAS disorder to a control group. METHODS: For this retrospective case-control study tissue from in total 77 abortion samples (healthy women, women with RPL and PAS disorder) were immunohistochemically stained and the above-mentioned cells and receptors were counted and statistically compared between the three groups with either Kruskal Wallis or ANOVA and corresponding posthoc tests. RESULTS: The number of EVTs was reduced in the RPL group. There were more dNK and PD-1dNK cells as well as a higher ratio of dNK cells compared to EVTs in the RPL group compared to the control group. Furthermore, the proportion of PD-L1 cells in all EVT cells was higher in the RPL group compared to the control group. CONCLUSION: Our findings show that both PD-1 and PD-L1 are differentially expressed on dNK cells and EVTs in the RPL group compared to the control group. Hereby suggesting that PD-1/PD-L1 interaction might influence NK cell function and therefore might be relevant for women experiencing RPL. This may be in terms of cytokine microenvironment or cell-cell-interaction.
The ever-expanding role of IFI16 in the anti-viral innate immune response.
Gewaid H, Bowie AG
Immunol Lett · 2026 Jun · PMID 41547462 · Publisher ↗
The host PYHIN (pyrin and HIN domain family) protein IFN-γ-inducible protein 16 (IFI16) was first discovered as a nuclear sensor of double-stranded DNA (dsDNA). Since then its roles in innate immunity have expanded to in...
The host PYHIN (pyrin and HIN domain family) protein IFN-γ-inducible protein 16 (IFI16) was first discovered as a nuclear sensor of double-stranded DNA (dsDNA). Since then its roles in innate immunity have expanded to include restriction of infection of both DNA and RNA viruses. Mechanistically, IFI16 restricts DNA viruses through four principal mechanisms: (i) direct repression of viral gene expression by binding viral genomes and promoting epigenetic-mediated silencing; (ii) sequestration of host transcription factor Sp1; (iii) induction of interferons (IFNs) after sensing viral genomes in the nucleus and cytosol; and (iv) assembly of apoptosis-associated speck-like protein containing a CARD (ASC)-dependent inflammasomes that activates caspase-1 leading to maturation of interleukin-1 beta (IL-1β) and interleukin-18 (IL-18) and pyroptosis. These mechanisms have been reported across dsDNA virus families, including Herpesviridae, Papillomaviridae, Hepadnaviridae, Parvoviridae, Polyomaviridae, and Poxviridae. For RNA viruses, IFI16 can: (i) directly bind viral genomes or sequester Sp1; (ii) amplify antiviral signalling by promoting RIG-I transcription or activation or cooperating with cyclic GMP-AMP synthase (cGAS)- stimulator of IFN genes (STING), and (iii) in some settings activate inflammasomes and pyroptosis. These mechanisms were reported for RNA virus families including, Togaviridae, Flaviviridae, Picornaviridae, Caliciviridae, Arteriviridae, Orthomyxoviridae, Paramyxoviridae and Retroviridae. Consistent with these antiviral roles, many viruses have evolved both destructive (IFI16 degradation) and non-destructive mechanisms to evade IFI16. This review summarizes the current understanding of how IFI16 mediates broad antiviral restriction and how diverse viruses subvert this role to facilitate their replication.
Control of regulatory T cell differentiation and function by glycan remodeling.
Wang Y, Shen Y, Liu K … +7 more , Liang R, Meng F, Zhang R, Jiang Z, Wang A, Chen J, Li Y
Immunol Lett · 2026 Jun · PMID 41529767 · Publisher ↗
Regulatory T (Treg) cells are indispensable for peripheral tolerance and immune homeostasis. Protein glycosylation plays an essential role in various cellular functions of T cells, including T cell development, thymocyte...
Regulatory T (Treg) cells are indispensable for peripheral tolerance and immune homeostasis. Protein glycosylation plays an essential role in various cellular functions of T cells, including T cell development, thymocyte selection, T cell activation and differentiation. Recently, many studies have explored the effects of glycosylation on Treg biology. Both N-linked glycosylation and O-linked glycosylation are important for the development, migration, suppressive function and lineage stability of Treg cells. In this review, we will discuss emerging evidence of glycosylation regulations on Treg cells and the developing technologies on the detection and analysis of unique glycan patterns and branching features. These efforts will help to reveal the function and regulatory roles of glycan remodeling in Treg cells, explore how glycan patterns modulate their phenotypes, and provide a strategic basis for clinical intervention and therapy of inflammatory diseases by targeting key glycosylation molecules in Treg cells.
Machine learning reveals sex-biased platelet-associated molecular signatures in systemic lupus erythematosus.
Li S, Ouyang H, Cui T … +5 more , Lin J, Wu K, Zhu E, Sui Y, Huang M
Immunol Lett · 2026 Jun · PMID 41506349 · Publisher ↗
OBJECTIVES: Autoimmune diseases (ADs) demonstrate a higher prevalence in women than men. Systemic Lupus Erythematosus (SLE) stands out among multiple ADs as an extreme case of the imbalanced sex ratio observed at disease...
OBJECTIVES: Autoimmune diseases (ADs) demonstrate a higher prevalence in women than men. Systemic Lupus Erythematosus (SLE) stands out among multiple ADs as an extreme case of the imbalanced sex ratio observed at disease onset, predominantly affecting females. This discrepancy can be ascribed to genetics, hormonal influences, environmental triggers, and more. Despite numerous studies aiming to uncover the sex differences in SLE, comprehensive bioinformatics integration for understanding its biological heterogeneity remains largely unexplored. METHODS: Transcriptomic data of 338 individuals (175 normal and 163 SLE) from the six SLE studies (GSE154851, GSE20864, GSE99967, GSE39088, GSE72754, and GSE81622) from the Gene Expression Omnibus were analyzed to uncover sex-specific candidate genes using differential gene expression analysis. Machine learning algorithms selected the candidate genes, and their performance was evaluated using receiver operating characteristic curves. Analyses were done by ADEx, GEO2R, and scRNA-seq. RESULTS: 72 enriched terms are shared between the female subgroup and the overall dataset, but none are shared between the male subgroup and the overall dataset. We identified differential expression of platelet glycoprotein VI (GP6) in male SLE, but not in the females, with GP6 predominantly expressed in platelets. Moreover, the correlation between GP6 and pre-T cell antigen receptor alpha (PTCRA) was significantly more pronounced in male SLE patients (r = 0.7004, p = 0.0053) compared to females (r = 0.5741, p < 0.0001). Additionally, GP6 and PTCRA were positively associated with Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) in male SLE patients, but not in females. CONCLUSIONS: There is a sex-based bias in SLE. GP6 marks a PTCRA-expressing platelet subset that is differentially altered in male SLE compared with controls, but not in female SLE, indicating a sex-dependent platelet molecular phenotype. The differential GP6 expression on PTCRA-expressing platelets between male and female SLE patients may contribute to differences in their clinical manifestations.
Escherichia coli J5-derived OMVs with hypoendotoxic LPS: Potential boosters of T-cell immunity and IL-17 production for enhanced vaccine efficacy.
Zhang J, Zhi Y, Yin W … +4 more , Wang H, Lu Y, Ma F, Wang D
Immunol Lett · 2026 Jun · PMID 41500265 · Publisher ↗
Lipopolysaccharide (LPS) is the core epitope of Escherichia coli (E. coli) J5 (O111:B4), a vaccine strain for bovine mastitis. It provides a significant protective effect in host suffering from Gram-negative bacteremia....
Lipopolysaccharide (LPS) is the core epitope of Escherichia coli (E. coli) J5 (O111:B4), a vaccine strain for bovine mastitis. It provides a significant protective effect in host suffering from Gram-negative bacteremia. However, LPS remains the main toxin in bacterial outer membrane vesicles (OMVs), which are non-replicative nanoparticles capable of robust immune modulation. Here, we focused on the immunomodulatory effect of hypoendotoxic LPS containing penta-acylated monophosphoryl lipid A on OMVs derived from E. coli J5. OMVs containing penta-acylated monophosphoryl LPS (referred to as mOMVs) induced a moderate inflammatory response. mOMVs still remained nanoparticle diameters of approximately 30 nm and 100 nm, facilitating antigen drainage to lymph nodes and presentation to dendritic cells (DCs). OMVs could stimulate cell aggregation at injection sites, conducive to DCs activation, with mOMVs enhancing CD3T cell proliferation and differentiation of CD4 and CD8T cell. Notably, CD4T cells activated by DCs primed with mOMVs produced higher levels of IL-17, suggesting potential enhanced mucosal immunity. Additionally, mOMVs elicited protective antibody responses against clinically isolated E. coli strain. These findings suggest that detoxified LPS endows OMVs with increased efficacy and safety, thereby further promoting the optimization of these vesicles for inducing cross-protection.
Enrichment of CD103 CD4 T cells in bone metastases compared to non-malignant controls.
Brauneck E, Kylies J, Assemissen AM … +8 more , Kruppa M, Kruppa N, Wahid Y, Brauneck F, Fiedler W, Viezens L, Wellbrock J, Leonhardt LG
Immunol Lett · 2026 Jun · PMID 41485718 · Publisher ↗
BACKGROUND: Bone metastasis (BoM) is a frequent complication of solid tumors, leading to poor prognosis and reduced survival. CD103⁺ tumor-infiltrating lymphocytes (TILs) are critical for antitumor immunity, yet studies...
BACKGROUND: Bone metastasis (BoM) is a frequent complication of solid tumors, leading to poor prognosis and reduced survival. CD103⁺ tumor-infiltrating lymphocytes (TILs) are critical for antitumor immunity, yet studies have largely focused on CD8⁺ subsets, leaving CD103⁺CD4⁺ cells poorly characterized. METHODS: Bone aspirates containing malignant cells were obtained from patients with symptomatic spinal and/or pelvic metastases of breast cancer (BC), prostate cancer (PC), or non-small cell lung cancer (NSCLC). Age-matched bone marrow samples from individuals without malignancy (NMCs) were controls. Multiparametric flow cytometry (MFC) was utilized to assess the expression of CD103 and exhaustion markers (TIGIT, PVRIG, KIR2DL5, CD39) in CD3 cells. RESULTS: CD103⁺CD3 T cells are significantly elevated in BoM compared to NMC, driven by an increase in CD103⁺CD4⁺ cells, despite a relative decrease in frequency of CD103⁺CD8⁺ cells. Furthermore, CD103CD4 cells from BoM displayed a significantly increased fraction of the central memory (CM) phenotype. Expression and coexpression of TIGIT, PVRIG, KIR2DL5 and CD39 on CD103 cells both in the CD4 and CD8 compartment was significantly increased in BoM, compared within CD103 within BoM and CD103 in NMC. CONCLUSION: In conclusion, BoM exhibit a distinct T-cell composition, highlighted by an increase in CD103⁺CD4⁺ cells displaying an increased CM phenotype. In BoM, cregulatory receptor expression is increased on CD103⁺ T cells, with distinct coexpression signatures in both CD4⁺ and CD8⁺ cells. Functional studies will determine whether targeting these checkpoint pathways can improve immunotherapy for metastatic bone disease.
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