Immunology letters最新文献

{"title":"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","authors":"Muñóz-Godínez Ricardo ,&nbsp;Monroy-García Alberto ,&nbsp;Hernández-Cueto Ángeles María ,&nbsp;García-Rocha Rosario ,&nbsp;Weiss-Steider Benny ,&nbsp;Hernández-Montes Jorge ,&nbsp;Don-López Christian Azucena ,&nbsp;Díaz Ramos Juan Antonio ,&nbsp;Pérez-Koldenkova Vadim ,&nbsp;Molina-Castillo Gabriela ,&nbsp;Mora-García María de Lourdes","doi":"10.1016/j.imlet.2026.107150","DOIUrl":"10.1016/j.imlet.2026.107150","url":null,"abstract":"<div><div>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+ <em>T</em> lymphocytes. In this study, we investigated the associations between PD-L1, CD73, and TGF-β expression and the percentage of PD-1-expressing CD8+ <em>T</em> 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 (<em>n</em> = 27), CIN-II (<em>n</em> = 25), CIN-III (<em>n</em> = 23), and CC (<em>n</em> = 23), in addition to ND tissue samples (<em>n</em> = 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 + <em>T</em> cells, increased in cervical tissues, correlating with disease progression. PD-L1 expression positively correlated with both CD73 (<em>r</em> = 0.8274, <em>p</em> &lt; 0.001) and TGF-β1 (<em>r</em> = 0.8535, <em>p</em> &lt; 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 (<em>r</em> = 0.7199, <em>p</em> &lt; 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).</div></div>","PeriodicalId":13413,"journal":{"name":"Immunology letters","volume":"280 ","pages":"Article 107150"},"PeriodicalIF":2.8,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146219162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association of computed tomography densitometry with disease progression and spatial heterogeneity in rheumatoid arthritis-associated interstitial lung disease","authors":"Zhinan Guo ,&nbsp;Yu Zhang ,&nbsp;Guanheng Li ,&nbsp;Nie Han ,&nbsp;Xingting Jiang ,&nbsp;Jiawei Ma ,&nbsp;Yayi Qin ,&nbsp;Diru Zhu ,&nbsp;Xiaoli Gu ,&nbsp;Lin Jin","doi":"10.1016/j.imlet.2026.107157","DOIUrl":"10.1016/j.imlet.2026.107157","url":null,"abstract":"<div><h3>Objectives</h3><div>This study aimed to assess the efficacy of quantitative computed tomography (qCT) in distinguishing rheumatoid arthritis-associated interstitial lung disease (RA-ILD) and monitoring its progression.</div></div><div><h3>Methods</h3><div>HRCT images of 138 RA-ILD patients (GAP_I, <em>n</em> = 90; GAP_II+III, <em>n</em> = 48) and 47 RA controls were retrospectively analyzed. The normal lung attenuation areas (NL%), the percentage of low attenuation areas (LAA%), and the percentage of high-attenuation areas (HAA%) were measured for each lung lobe. Correlations between qCT indices and pulmonary function tests were evaluated using Spearman’s rank correlation. ROC curves tested the discriminative performance of qCT indices. Multivariable logistic regression assessed associations between qCT indices and RA-ILD.</div></div><div><h3>Results</h3><div>The NL% decreased, while the LAA% and HAA% increased in the early and moderate-to-advanced stages of ILD, respectively (<em>p</em> &lt; 0.05). Multivariate regression identified HAA% as an independent risk factor for ILD staging (OR: 1.737, 95% CI: 1.182–2.551, <em>p</em> = 0.005). When combining NL%, LAA%, and HAA%, the AUCs for early diagnosis and progression monitoring were 0.760 and 0.773, respectively (<em>p</em> &lt; 0.05). RA-ILD exhibited spatial heterogeneity, with the lower lobes being primarily affected.</div></div><div><h3>Conclusions</h3><div>Quantitative parameters can effectively differentiate early-stage RA-ILD and monitor its progression. LAA% is significantly correlated with early diagnosis, whereas HAA% demonstrates higher specificity in later stages. Quantitative lung densitometry may prove to be a valuable tool for clinical decision-making.</div></div>","PeriodicalId":13413,"journal":{"name":"Immunology letters","volume":"280 ","pages":"Article 107157"},"PeriodicalIF":2.8,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147344087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vitamin D ameliorates NETosis and Th17/Treg imbalance in experimental autoimmune thyroiditis","authors":"Hai-Yan Yang ,&nbsp;Xi-Zhen Wu ,&nbsp;Yu-Ping Liu ,&nbsp;Gui-Yang Jiang ,&nbsp;Ying-Fen Qin ,&nbsp;Xing-Huan Liang ,&nbsp;Zuo-Jie Luo","doi":"10.1016/j.imlet.2026.107156","DOIUrl":"10.1016/j.imlet.2026.107156","url":null,"abstract":"<div><h3>Background</h3><div>Neutrophil extracellular traps (NETs) have been implicated in various autoimmune diseases; however, their role in Hashimoto's thyroiditis (HT) remains poorly understood. This study aimed to characterize NETs formation, explore its association with thyroid dysfunction and adaptive immunity, and evaluate the therapeutic potential of vitamin D (VD) in experimental autoimmune thyroiditis (EAT).</div></div><div><h3>Methods</h3><div>EAT was induced in BALB/c mice via thyroglobulin immunization combined with excess iodine intake. The VD group received additional intraperitoneal calcitriol supplementation. Thyroid histopathology, MHC-II expression, thyroid antibodies (TGAb and TPOAb), plasma DNase-I and 1,25(OH)₂D₃ levels, NETs formation, and splenic T cell subsets (Th17, Treg, Th1, Th2) and cytokines were assessed. Parallel experiments were conducted using neutrophils isolated from HT patients.</div></div><div><h3>Results</h3><div>Neutrophils from both EAT mice and HT patients exhibited enhanced NETosis compared to controls. EAT mice showed lower levels of DNase-I, 1,25(OH)₂D₃, Treg, and Th1 cells, along with higher Th17 and Th2 cells, elevated Th17/Treg ratio, and heightened thyroid MHC-II expression. NETs levels positively correlated with Th17, Th2, and MHC-II expression, and negatively with Treg, Th1, 1,25(OH)₂D₃, and DNase-I. VD supplementation mitigated thyroiditis and TPOAb levels, suppressed NETs formation, and reduced the Th17/Treg ratio and IL-17 levels.</div></div><div><h3>Conclusions</h3><div>NETs contribute to Th17 bias and MHC-II over-expression in HT, suggesting a role in shaping the adaptive immune response. Vitamin D restrains NETosis and restores T-cell homeostasis, highlighting its potential as an adjunctive therapy for HT.</div></div>","PeriodicalId":13413,"journal":{"name":"Immunology letters","volume":"280 ","pages":"Article 107156"},"PeriodicalIF":2.8,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147344083","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Src-family kinase control of CAR signaling: the paradoxical and multifaceted role of LCK","authors":"Luca Simeoni ,&nbsp;Dimitrios Mougiakakos ,&nbsp;Stephan Fricke","doi":"10.1016/j.imlet.2026.107158","DOIUrl":"10.1016/j.imlet.2026.107158","url":null,"abstract":"<div><div>Lymphocyte-specific protein tyrosine kinase (LCK) is central to early T-cell receptor (TCR) signaling and is tightly regulated by phosphorylation, protein–protein interactions, and spatial organization to control T-cell activation and fate. Chimeric antigen receptors (CARs) co-opt core elements of the TCR signaling machinery, including LCK. Nevertheless, important mechanistic differences, which remain largely unexplored, exist in how LCK is recruited, activated, and restrained during CAR signaling relative to canonical TCR signaling. Accumulating evidence indicates that CAR architecture, particularly the nature and organization of costimulatory signaling domains, profoundly influences LCK activity, signal strength, tonic signaling, and downstream differentiation outcomes. Excessive or sustained LCK activity can drive metabolic stress and exhaustion, whereas limiting or fine-tuning LCK signaling improves CAR T-cell persistence and therapeutic efficacy. Here, we review the current understanding of LCK regulation in CAR signaling and highlight recent insights into pharmacologic and structural strategies to tune LCK activity. A deeper understanding of LCK regulation is essential for improving the efficacy and safety of CAR T cells and may help in the design of next-generation CARs.</div></div>","PeriodicalId":13413,"journal":{"name":"Immunology letters","volume":"280 ","pages":"Article 107158"},"PeriodicalIF":2.8,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147365147","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Control of regulatory T cell differentiation and function by glycan remodeling","authors":"Yanwen Wang ,&nbsp;Yunyue Shen ,&nbsp;Kaini Liu ,&nbsp;Rui Liang ,&nbsp;Fangkang Meng ,&nbsp;Rongliang Zhang ,&nbsp;Ziqi Jiang ,&nbsp;Aiting Wang ,&nbsp;Jieqiong Chen ,&nbsp;Yangyang Li","doi":"10.1016/j.imlet.2026.107138","DOIUrl":"10.1016/j.imlet.2026.107138","url":null,"abstract":"<div><div>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 <em>N-</em>linked glycosylation and <em>O-</em>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.</div></div>","PeriodicalId":13413,"journal":{"name":"Immunology letters","volume":"279 ","pages":"Article 107138"},"PeriodicalIF":2.8,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145966066","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Escherichia coli J5-derived OMVs with hypoendotoxic LPS: Potential boosters of T-cell immunity and IL-17 production for enhanced vaccine efficacy","authors":"Jiawen Zhang ,&nbsp;Yuhang Zhi ,&nbsp;Wenzhu Yin ,&nbsp;Haiyan Wang ,&nbsp;Yu Lu ,&nbsp;Fang Ma ,&nbsp;Deyun Wang","doi":"10.1016/j.imlet.2026.107137","DOIUrl":"10.1016/j.imlet.2026.107137","url":null,"abstract":"<div><div>Lipopolysaccharide (LPS) is the core epitope of <em>Escherichia coli</em> (<em>E. coli</em>) 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 <em>E. coli</em> 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 CD3⁺ <em>T</em> cell proliferation and differentiation of CD4⁺ and CD8⁺ <em>T</em> cell. Notably, CD4⁺ <em>T</em> 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 <em>E. coli</em> 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.</div></div>","PeriodicalId":13413,"journal":{"name":"Immunology letters","volume":"279 ","pages":"Article 107137"},"PeriodicalIF":2.8,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145917523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Compartment-specific activation of kinin B1 and B2 receptors drives the production of vasoactive and inflammatory mediators during SARS-CoV-2 infection","authors":"Jéssica Dotto de Lara ,&nbsp;Taís Vidal ,&nbsp;Julia Brandt de Souza ,&nbsp;Elyan Kodavara ,&nbsp;Eduardo Reichert Decker ,&nbsp;Fabielly Scolari Grotto ,&nbsp;Luisa Donato Bortoluzzi ,&nbsp;Ana Paula Santini dos Santos ,&nbsp;Indiara Brusco ,&nbsp;Sara Marchesan de Oliveira ,&nbsp;Fernanda Tibolla Viero ,&nbsp;Talita Glaser ,&nbsp;Leandre Carmem Wilot ,&nbsp;Thissiane de Lima Gonçalves Bernasconi ,&nbsp;Andressa de Azambuja Pias Weber ,&nbsp;Daniele Rubert Nogueira Librelotto ,&nbsp;Maiele Dornelles Silveira ,&nbsp;Nathalia Denise de Moura Sperotto ,&nbsp;Henning Ulrich ,&nbsp;Luiz Augusto Basso ,&nbsp;Micheli Mainardi Pillat","doi":"10.1016/j.imlet.2025.107125","DOIUrl":"10.1016/j.imlet.2025.107125","url":null,"abstract":"<div><div>Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) disrupts multiple host regulatory systems, including the kallikrein–kinin system (KKS), which plays a central role in vascular homeostasis and inflammation. Following viral entry, angiotensin-converting enzyme 2 (ACE2) is internalized and inactivated, impairing the degradation of des-Arg⁹-bradykinin (DABK), a selective agonist of the inducible kinin B1 receptor (B1R), while inflammatory feedback mechanisms may further elevate bradykinin (BK), the kinin B2 receptor (B2R) agonist. It has been postulated that the kinin storm observed in COVID-19 patients may lead to pulmonary angioedema, promote the exacerbated production of pro-inflammatory cytokines, and be related to disease progression, permanent sequelae, and death. However, it remains unknown whether <em>in vitro</em> SARS-CoV-2 infection triggers alterations in the KKS and its downstream inflammatory and vasoactive mediators. Here, we investigated how SARS-CoV-2 infection modulates kinin signaling and its downstream inflammatory and vasoactive mediators in Vero E6 and human endothelial (HUVEC) cells. SARS-CoV-2 infection increased BK levels and markedly upregulated B1R gene expression in Vero E6 cells (up to 20-fold), while B2R expression remained unchanged. Both BK and DABK reduced ACE2 expression in Vero E6 cells, an effect most likely mediated by DABK–B1R signaling due to the minimal expression of B2R in this cell line. Viral infection induced robust production of nitric oxide (NO) and interleukin-6 (IL-6) in Vero E6 cells, and supernatants from infected cells triggered similar responses in HUVECs. Pharmacological blockade of B1R with R-715 selectively prevented SARS-CoV-2–induced NO production in Vero E6 cells, whereas IL-6 induction occurred through B1R-independent mechanisms. In contrast, in endothelial HUVEC cells exposed to serum from patients with severe COVID-19, B2R antagonism with HOE-140 prevented both NO and IL-6 production, suggesting a key role for B2R in both vascular cytokine amplification and vasoactive mediator production. Our findings reveal a compartment-specific and complementary activation of B1R and B2R during SARS-CoV-2 infection, establishing the KKS as a key mediator of endothelial alterations and inflammatory amplification in COVID-19 and positioning B1R and B2R as therapeutic targets.</div></div>","PeriodicalId":13413,"journal":{"name":"Immunology letters","volume":"279 ","pages":"Article 107125"},"PeriodicalIF":2.8,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145804259","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enrichment of CD103+ CD4+ T cells in bone metastases compared to non-malignant controls","authors":"Elias Brauneck ,&nbsp;Julian Kylies ,&nbsp;Anne Marie Assemissen ,&nbsp;Moritz Kruppa ,&nbsp;Niklas Kruppa ,&nbsp;Yagana Wahid ,&nbsp;Franziska Brauneck ,&nbsp;Walter Fiedler ,&nbsp;Lennart Viezens ,&nbsp;Jasmin Wellbrock ,&nbsp;Leon-Gordian Leonhardt","doi":"10.1016/j.imlet.2026.107135","DOIUrl":"10.1016/j.imlet.2026.107135","url":null,"abstract":"<div><h3>Background</h3><div>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.</div></div><div><h3>Methods</h3><div>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.</div></div><div><h3>Results</h3><div>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, CD103⁺CD4⁺ 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.</div></div><div><h3>Conclusion</h3><div>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.</div></div>","PeriodicalId":13413,"journal":{"name":"Immunology letters","volume":"279 ","pages":"Article 107135"},"PeriodicalIF":2.8,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145900431","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The ever-expanding role of IFI16 in the anti-viral innate immune response","authors":"Hossam Gewaid ,&nbsp;Andrew G. Bowie","doi":"10.1016/j.imlet.2026.107139","DOIUrl":"10.1016/j.imlet.2026.107139","url":null,"abstract":"<div><div>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 <em>Herpesviridae, Papillomaviridae, Hepadnaviridae, Parvoviridae, Polyomaviridae</em>, and <em>Poxviridae</em>. 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, <em>Togaviridae, Flaviviridae, Picornaviridae, Caliciviridae, Arteriviridae, Orthomyxoviridae, Paramyxoviridae</em> and <em>Retroviridae</em>. 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.</div></div>","PeriodicalId":13413,"journal":{"name":"Immunology letters","volume":"279 ","pages":"Article 107139"},"PeriodicalIF":2.8,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145994195","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LCK at the crossroad of immunodeficiency and autoimmunity: Mechanisms and therapeutic opportunities","authors":"Nadine M. Woessner ,&nbsp;Baerbel Keller ,&nbsp;Susana Minguet","doi":"10.1016/j.imlet.2025.107126","DOIUrl":"10.1016/j.imlet.2025.107126","url":null,"abstract":"<div><div>The lymphocyte-specific protein tyrosine kinase (LCK) is the principal initiator of T cell receptor (TCR) signaling and a critical regulator of T-cell development, activation, and immune tolerance. Its critical expression in T cells positions LCK as both a molecular gatekeeper of adaptive immunity and an attractive therapeutic target. Loss-of-function mutations in LCK result in combined immunodeficiency with profound defects in T-cell differentiation and signaling, whereas hypomorphic variants with residual activity can promote immune dysregulation and autoimmunity. Conversely, aberrant LCK activation is associated with autoimmunity and chronic inflammation, including type 1 diabetes, psoriasis, rheumatoid arthritis, asthma, multiple sclerosis, and graft-<em>versus</em>-host disease. Here, we review the structural and regulatory mechanisms of LCK, its dysfunction in immunodeficiency and autoimmunity, and the current landscape of therapeutic strategies. While first-generation inhibitors targeting the ATP-binding site have shown efficacy in preclinical models, their lack of selectivity highlights the need for innovative approaches directed at non-catalytic domains of LCK. By linking mechanistic understanding with clinical relevance, we position LCK as a precision regulatory node with the potential to transform therapeutic strategies for T cell-driven immune disorders.</div></div>","PeriodicalId":13413,"journal":{"name":"Immunology letters","volume":"279 ","pages":"Article 107126"},"PeriodicalIF":2.8,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145892225","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}