Cellular Immunology[JOURNAL]
Sun
200 papers
Thymidine induces macrophage M1 polarization in radiation-induced-lung-injury by ATF3/p38 pathway.
Fan H, Ge X, Zhou X … +7 more , Zhang P, Li Y, Du Z, Cheng D, Lu Y, Liu Q, Hu Y
Cell Immunol · 2026 Apr · PMID 41698309 · Publisher ↗
Radiation-induced lung injury (RILI) arises as a critical complication of thoracic radiotherapy, characterized by unresolved inflammation and macrophage-driven alveolar damage. While metabolic dysregulation post-radiatio...
Radiation-induced lung injury (RILI) arises as a critical complication of thoracic radiotherapy, characterized by unresolved inflammation and macrophage-driven alveolar damage. While metabolic dysregulation post-radiation is implicated in macrophage polarization, the precise immunometabolic triggers remain undefined. Here, we uncover thymidine-a radiation-elevated metabolite released by injured lung epithelia-as an important regulator of M1 macrophage polarization through multi-omics dissection. Critically, thymidine dietary restriction or AAV9 (Adeno-associated Virus, AAV)-delivered ATF3 in murine models reversed this pathogenic loop, reducing M1 polarization and attenuating pneumonitis. Transcriptomic profiling of irradiated macrophages exposed to thymidine revealed ATF3 suppression and MAPK hyperactivation, establishing a feedforward ATF3/p38 axis that induces epithelial injury. ATF3 overexpression or pharmacological p38 inhibition (SB203580) reversed thymidine's pro-inflammatory reprogramming in vitro. These findings position the thymidine-ATF3/p38 circuit as a lynchpin of radiation-associated immunopathology and advocate metabolic or transcriptional intervention as a viable adjunct to conventional radioprotection strategies.
Clarifying diagnostic rigor and cohort characteristics in neurosyphilis nomogram development: a response to Kenyon.
Ling Y
Cell Immunol · 2026 Apr · PMID 41666792 · Publisher ↗
Abstract loading — click title to view on PubMed.
Cellular immune response following homologous and heterologous BNT162b2 booster vaccination after primary immunization with BNT162b2 and CoronaVac respectively.
Siti Asmaa MJ, Sasikaran DS, Yassim ASM … +8 more , Rosdan BSM, Asri AAM, Hisham AAM, Suppian R, Idris NS, Muhamad R, Azlan M, Norazmi MN
Cell Immunol · 2026 Jan · PMID 41654469 · Publisher ↗
Several vaccines targeting SARS-CoV-2 were developed following the COVID-19 outbreak. However, subsequent studies have indicated that humoral immune responses wane over time, particularly with the emergence of new SARS-C...
Several vaccines targeting SARS-CoV-2 were developed following the COVID-19 outbreak. However, subsequent studies have indicated that humoral immune responses wane over time, particularly with the emergence of new SARS-CoV-2 variants. There is limited understanding of the resilience of T cell-mediated immunity induced by COVID-19 vaccines. This prospective cohort study involved a population who completed two primary doses of either the Pfizer BNT162b2 mRNA vaccine (PP) or the Sinovac Coronavac inactivated virus vaccine (SS) followed by one homologous (PPP) or heterologous (SSP) booster dose of BNT162b2, through convenience sampling of healthy adults. Blood samples were collected at three intervals, 2-weeks (T1), 6-8 months (T2), and 12-months (T3) following the booster immunization. Immunophenotyping was performed to evaluate T cell activity, memory, and intracellular cytokines at each timepoint. Our study found that the expression of T cell activation markers by both CD4+ and CD8+ T cells, such as CD25 + CD69+ and CD38 + HLA-DR+ was significantly higher at T2 compared to T1 in both PPP and SSP groups, indicating a robust T cell activation post-booster vaccination. Memory T cell subsets, including central memory and stem cell memory T cells, exhibited distinct kinetics, with both vaccines showing sustained levels of selected memory T cell subsets right up to about one year after booster. Furthermore, intracellular cytokine analysis revealed that CD4+ and CD8+ T cells in the SSP group exhibited higher level of IL-2, TNF-α and IFN-γ at specific timepoints, suggesting a stronger cellular immune response. These findings highlight the durability and qualitative differences in T cell-mediated immunity between homologous and heterologous vaccination regimens. While cellular immunity persisted in both groups up to 12 months post-booster, a decline in T3 underscores the potential, targeted need for additional booster doses to maintain protection against emerging SARS-CoV-2 variants.
Ibrutinib enhances stem-cell-memory T cell generation during early T cell activation but inhibits T cell proliferation.
He L, Liu Y, Zhou J … +4 more , Zhang T, Zhang S, Ge J, Hong J
Cell Immunol · 2026 Jan · PMID 41650529 · Publisher ↗
Ibrutinib has been demonstrated to restore T cell immunity of chronic lymphocytic leukemia patients, and enhance ex vivo expansion and function of CAR-T cells. In attempt to explore the effect of ibrutinib on unmanipulat...
Ibrutinib has been demonstrated to restore T cell immunity of chronic lymphocytic leukemia patients, and enhance ex vivo expansion and function of CAR-T cells. In attempt to explore the effect of ibrutinib on unmanipulated T cells, we activated human PBMCs from healthy donors with CD3/CD28 stimulation and cultured them with or without ibrutinib under various conditions. Phenotypic and functional assessments were then performed using flow cytometry. Results showed that ibrutinib could downregulate programmed cell death protein 1 expression and reduce activation-induced cell death of T cells. Additionally, ibrutinib added at the onset of T cell activation, rather than 48 h later, could further promote the generation of CD45RACCR7CD95 stem-cell-memory T cell subset in the presence of IL-7 and IL-15. However, ibrutinib also suppressed the proliferation and cytokine-secretion capacity of T cells in a dose-dependent manner. Further RNA sequencing of activated CD8 T cells demonstrated that ibrutinib administration at the onset of T cell activation modulated multiple TCR downstream signaling pathways, notably downregulating mTORC1 signaling and upregulating FOXO1 signaling. In contrast, ibrutinib added 48 h post-activation did not show these effects. These findings suggest that caution should be exercised when incorporating ibrutinib into ex vivo expansion system for adoptive non-genetically engineered T cells or combining ibrutinib with these T cell immunotherapies in clinical trial settings.
TREM2 promotes susceptibility to colitis through the induction of gut microbiota dysbiosis.
Seo JE, Seon JE, Yee SM … +7 more , Koo HS, Moon SH, Seo HJ, Seo JH, Kim SM, Choi H, Kang HS
Cell Immunol · 2026 Jan · PMID 41564685 · Publisher ↗
Triggering receptor expressed on myeloid cells 2 (TREM2) has been implicated in the pathogenesis of inflammatory bowel disease (IBD), yet its role in microbiota-mediated intestinal immune homeostasis remains incompletely...
Triggering receptor expressed on myeloid cells 2 (TREM2) has been implicated in the pathogenesis of inflammatory bowel disease (IBD), yet its role in microbiota-mediated intestinal immune homeostasis remains incompletely defined. Here, we demonstrate that TREM2 expression is associated with exacerbated colonic inflammation in a murine model of DSS-induced colitis, disrupting epithelial integrity and microbial homeostasis. TREM2 transgenic (TG) mice developed more severe disease and mucosal injury, accompanied by marked dysbiosis characterized by the expansion of pro-inflammatory taxa (Firmicutes, Actinobacteria, Prevotella) and depletion of beneficial commensals (Lactobacillus, Bifidobacterium). This TREM2-driven dysbiotic and inflammatory state was associated with region-specific suppression of antimicrobial peptide (AMP) expression in the gut, elevated production of pro-inflammatory cytokines and reactive oxygen species (ROS), and a diminished frequency of IL-17A-producing Th17 cells in the colon. Conversely, TREM2 knockout (KO) mice preserved microbial composition, strengthened epithelial defenses, and attenuated inflammatory responses. Collectively, these findings establish TREM2 as a pivotal regulator of gut immune-microbial interactions and demonstrate its potential as a therapeutic target in IBD.
An accurate predictive neurosyphilis scoring system depends on an accurate diagnosis of neurosyphilis.
Chris K
Cell Immunol · 2026 Jan · PMID 41539124 · Publisher ↗
Abstract loading — click title to view on PubMed.
Functional and structural analysis of KK-LC-1-specific T cell receptors from patients with lung Cancer for immunotherapy.
Fukushima Y, Wang Y, Yada-Makino Y … +21 more , Komuro H, Demachi-Okamura A, Sugita Y, Okamoto T, Ishihara H, Mizuta R, Sun Y, Matsui T, Araki M, Biao M, Okuno Y, Masago K, Yamaguchi R, Guo Z, Onoguchi K, Yamashita Y, Fukuyama T, Nabekura T, Matsushita H, Iwata H, Muraoka D
Cell Immunol · 2026 Jan · PMID 41500040 · Publisher ↗
Adoptive T-cell receptor (TCR)-engineered T cell therapy is a promising approach for cancer immunotherapy, particularly for cancer/testis antigens such as KK-LC-1. We evaluated four KK-LC-1 epitope-specific TCRs restrict...
Adoptive T-cell receptor (TCR)-engineered T cell therapy is a promising approach for cancer immunotherapy, particularly for cancer/testis antigens such as KK-LC-1. We evaluated four KK-LC-1 epitope-specific TCRs restricted by Human Leukocyte Antigen (HLA)-B*15:01, including three identified by our group and one previously reported. Their properties were characterised using TCRαβ-transduced γδT and Jurkat cells through functional analyses, including IFN-γ production, activation marker expression, cytotoxicity, TCR signalling, and T cell-target cell interactions, complemented by molecular dynamics simulations. One TCR exhibited superior performance, with the highest IFN-γ production, activation marker expression, and cytotoxicity, sustaining robust TCR signalling at low antigen levels and enhancing T cell-target interactions. Molecular dynamics simulations revealed that it exhibited a high binding affinity and stable interface, characterised by hydrogen bonds evenly distributed across the peptide and HLA α1/α2 helices, likely contributing to the conformational stability of the TCR-pMHC complex. These findings suggest that the functional superiority of this TCR is attributable to its structurally balanced and stable engagement with the pMHC complex. This study highlights the structural basis of TCR efficacy and provides a practical framework for optimising TCR selection for adoptive immunotherapy.
BCG and β-glucan primed monocytes yield dendritic cells that hamper the induction of pro-inflammatory T cell immunity.
Cuenca-Escalona J, Kramer R, Marjalizo-Jimenez C … +5 more , Domínguez-Andrés J, Netea MG, Flórez-Grau G, de Vries IJM, Horrevorts SK
Cell Immunol · 2026 Jan · PMID 41500039 · Publisher ↗
Dendritic cells (DCs) are professional antigen-presenting cells that regulate inflammatory and tolerogenic immunity. Their role within trained immunity, a process in which innate immune cells exhibit memory-like characte...
Dendritic cells (DCs) are professional antigen-presenting cells that regulate inflammatory and tolerogenic immunity. Their role within trained immunity, a process in which innate immune cells exhibit memory-like characteristics, remains to be elucidated. To date, increasing evidence indicates that trained immunity underlies the enhanced innate immune response induced by the Bacillus Calmette-Guérin (BCG) vaccine and the fungal cell wall component β-glucan (β-Glc), contributing to protection against heterologous infections and cancer. Concurrently, preclinical evidence suggests that BCG can also attenuate the severity of autoimmunity. Given the unclear immunomodulatory effects of these compounds on DCs we investigated the effects of BCG and β-Glc on human monocyte-derived DCs (moDCs). Our results demonstrate that early exposure to BCG and β-Glc during moDC development steers their function towards tolerance, indicated by reduced pro-inflammatory cytokine production upon rechallenge. Additionally, BCG and β-Glc challenge hampered the moDCs' ability to mount proinflammatory IFN-γ-driven T cell responses, while mediating the enrichment of regulatory T cells. Metabolically, we potentially observe signs that BCG amplifies glycolysis but not oxidative phosphorylation. Together, our findings provide novel insights into the role of BCG and β-Glc on human DCs and support the therapeutic potential of modulating human DCs with these training agents for the treatment of autoimmune disorders.
Vitiligo immunopathogenesis: Insight of immune components and prospects of emerging immunotherapies.
Tembhre MK, Khan WH
Cell Immunol · 2026 · PMID 41435724 · Publisher ↗
Vitiligo is an acquired depigmenting disease characterized by the loss of pigmentation from the skin due to selective killing of pigment forming cells (melanocytes) by cytotoxic T cells (CD8+ T cells). The pathogenesis o...
Vitiligo is an acquired depigmenting disease characterized by the loss of pigmentation from the skin due to selective killing of pigment forming cells (melanocytes) by cytotoxic T cells (CD8+ T cells). The pathogenesis of vitiligo has broad spectrum ranging from genetic, biochemical and immunological factors. Based on these multifactorial aetiologies several hypotheses have been suggested with substantial evidence. Recent advances in the understanding of immunopathogenesis of the disease have opened new avenues that may be translated into effective treatment strategies. There is requirement of new immunomolecular targets aiming to reinstate the skin homeostasis by maintaining the fine tuning with immune parameters and melanocyte microenvironment of the skin. The present review will address the recent advances in the pathogenesis of generalized vitiligo (GV) giving emphasis on memory T cells, regulatory T cells (Tregs), cytokines and chemokines with prospects of promising immunotherapies.
Pan-organ damage analysis in the R848-induced systemic lupus erythematosus mouse model.
Li X, Bao C, Xu M … +2 more , Sun L, Chen H
Cell Immunol · 2026 · PMID 41365211 · Publisher ↗
BACKGROUND: Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease that often leads to organ dysfunction. Resiquimod (R848) can induce the establishment of SLE models in mice within a relatively short per...
BACKGROUND: Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease that often leads to organ dysfunction. Resiquimod (R848) can induce the establishment of SLE models in mice within a relatively short period. However, there are few comprehensive systematic research reports on the degree and differences of organ involvement in this model. Therefore, the aim of this study was to clarify the systemic involvement of the SLE model induced by R848. METHODS: C57BL/6 mice were treated with 2 μg/μL R848 for 4 weeks. After the last administration, H&E staining was used to examine pathological changes in multiple organs (bone, thymus, spleen, knee joints, kidney, etc.). Real-time quantitative PCR (RT-qPCR) and western blotting were used to detect the mRNA and protein levels of toll-like receptors (TLRs) and inflammatory factors. Flow cytometry analysis was performed to examine the changes in T- and B-cell subsets within the spleen. Immunofluorescence was used to analyse immune complex deposition in the kidneys. RESULTS: R848 successfully induced an SLE mouse model characterized by splenomegaly, elevated serum levels of anti-dsDNA antibodies, immune complex deposition in the kidneys, and imbalanced T-/B- cell populations, etc. Severe pathological changes were detected in specific organs, such as the bone, thymus, spleen, and knee joint, whereas no obvious lesions were observed in organs, such as the heart. Accordingly, the Tlr7/8/9 pathway and its downstream inflammatory factor targets (Tnf, Ifng, Il6, and Il10) presented organ-specific expression profiles at the transcriptional level and the western blotting confirmed that the protein levels of TLR7/8 and TNF-α increased particularly in the spleen, but not in the kidney or submandibular gland. CONCLUSION: R848-induced SLE mice exhibit systemic immune disorders, with differences in pan-organ damage, inflammatory cell infiltration, and TLR7/8-mediated inflammatory factor expression. This study provides a foundation for clarifying the multisystem mechanism of SLE.
Chilean Phaseolus vulgaris landraces: A dietary source influencing NETs formation and phagocytic efficiency.
Ortiz-Salazar C, Hernández-Barros C, Tellería F … +10 more , Burgos CF, Trostchansky A, Plaza A, Carrasco B, Espinoza-Robles C, Blanco N, Wehinger S, Palomo I, Fuentes E, Alarcón L M
Cell Immunol · 2026 · PMID 41365210 · Publisher ↗
Neutrophil extracellular traps (NETs) are crucial for the antimicrobial defense; however, their dysregulated expression can lead to enhanced inflammation and tissue damage. NET formation requires reactive oxygen species...
Neutrophil extracellular traps (NETs) are crucial for the antimicrobial defense; however, their dysregulated expression can lead to enhanced inflammation and tissue damage. NET formation requires reactive oxygen species (ROS), particularly those generated through the NADPH oxidase (NOX2) pathway. This study investigates the immunomodulatory effects of aqueous extracts of Chilean landraces of Phaseolus vulgaris L. (Hallado Alemán) with microwave-assisted extraction, on ROS-dependent NETosis and phagocytosis. Using an in vitro model of differentiated HL-60 neutrophil-like cells and human polymorphonuclear neutrophils (PMNs) stimulated with PMA, we evaluated ROS production, NETs release, myeloperoxidase (MPO) activity, and cf-DNA release, as well as phagocytic activity. All experiments were performed in triplicate (n = 3 independent biological replicates); data are presented as mean ± SEM. Both extracts have high polyphenol content and effectively inhibit superoxide production and NET release without cytotoxic effects and increase bacterial phagocytosis. The extract components, including gallic acid, quercetin, and kaempferol, were confirmed by HPLC-DAD. In silico docking analysis showed robust binding of the same polyphenols to key inflammatory-regulating proteins, including PKCb, NOX2, and TLR4/MD2. These findings suggest that aqueous extracts of Phaseolus vulgaris modulate neutrophil function by attenuating proinflammatory responses while preserving antimicrobial activity, indicating their value as natural innate immune modulators.
Peiminine modulates T cell-associated gene expression and inflammatory activity in experimental autoimmune hepatitis.
Azizan A, Abyazi MA, Aghayan SK … +3 more , Mirzaei Nodooshan M, Ghorbani Alvanegh A, Esmaeili Gouvarchin Ghaleh H
Cell Immunol · 2026 · PMID 41289932 · Publisher ↗
Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease characterized by immune-mediated hepatocellular injury and insufficient regulatory T cell (Treg) control. Despite the efficacy of corticosteroids and aza...
Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease characterized by immune-mediated hepatocellular injury and insufficient regulatory T cell (Treg) control. Despite the efficacy of corticosteroids and azathioprine, incomplete response, side effects, and relapse often limit treatment, underscoring the need for novel therapeutic strategies. To date, little is known about the potential of natural compounds in modulating T cell-related pathways in AIH. This study aimed to evaluate the therapeutic effects of peiminine, an alkaloid with reported anti-inflammatory and immunomodulatory properties, in an experimental model of AIH. We investigated its impact on liver histopathology, inflammatory markers, and expression of T cell-associated genes (FOXP3, Tbx21, and RORc), comparing its efficacy with prednisolone. Our results demonstrated that peiminine treatment significantly alleviated interface hepatitis, reduced inflammatory cell infiltration, and improved lobular architecture. Quantitative histological scoring confirmed that peiminine, particularly at higher doses, exerted protective effects comparable to prednisolone. At the molecular level, peiminine increased FOXP3 expression while suppressing Tbx21 and RORc, suggesting restoration of Treg/Th1/Th17 balance. These findings were consistent with reductions in pro-inflammatory cytokine expression and improved liver function indices. Collectively, our findings provide promising preclinical evidence that peiminine can attenuate autoimmune-mediated liver injury by modulating T cell-associated immune pathways. While further validation in human studies is necessary, these results identify peiminine as a potential adjunct or alternative therapeutic candidate for AIH, with implications for broader autoimmune disease management.
Actin cytoskeleton stabilization inhibits NLRP3 inflammasome activation and mitigates renal inflammation and fibrosis in obstructive nephropathy.
Xu Q, Li J, Wan X … +6 more , Wang G, Wu J, Chang X, Yan F, Li L, Han B
Cell Immunol · 2026 · PMID 41285084 · Publisher ↗
Obstructive nephropathy is characterized by progressive renal inflammation and tubular injury, in which the NLRP3 inflammasome plays a pivotal role. However, the contribution of cytoskeletal dynamics to inflammasome acti...
Obstructive nephropathy is characterized by progressive renal inflammation and tubular injury, in which the NLRP3 inflammasome plays a pivotal role. However, the contribution of cytoskeletal dynamics to inflammasome activation remains poorly understood. In this study, we investigated whether stabilizing the actin cytoskeleton using Bis-T-23, a filamentous actin (F-actin) stabilizer, could alleviate renal injury by suppressing NLRP3 signaling. In a unilateral ureteral obstruction (UUO) mouse model, Bis-T-23 treatment significantly reduced tubular dilation, interstitial fibrosis, and immune cell infiltration. Transcriptomic profiling revealed marked downregulation of inflammation-related pathways, including TNF, IL-17, and NOD-like receptor signaling. At the molecular level, Bis-T-23 inhibited NLRP3 inflammasome activation, as evidenced by decreased levels of NLRP3, cleaved caspase-1, IL-1β, and IL-18 in both renal tissue and tubular epithelial cells. In vitro, TNFα/TGFβ1 co-stimulation induced a pro-fibrotic and pro-inflammatory phenotype in tubular cells, characterized by ZO-1 disruption, α-SMA upregulation, and enhanced NLRP3 expression, all of which were reversed by Bis-T-23. Furthermore, Bis-T-23 impaired ASC speck formation and disrupted NLRP3-ASC interactions, suggesting a direct blockade of inflammasome assembly. These findings identify cytoskeletal stabilization as a novel upstream mechanism for NLRP3 regulation and highlight Bis-T-23 as a potential therapeutic candidate for mitigating tubular inflammation in obstructive kidney disease.
Exosomes derived from ovarian cancer promote the progression of ovarian cancer through macrophage M2 polarization mediated by the THBS1/TGFBI signaling axis.
Yang L, Jia Y, Liu Y … +15 more , Wang S, Tan S, Ruan Y, Zhao L, Zhao H, Xu R, Ding C, Liu H, Qin Y, Zhao H, Feng X, Zeng C, Li Y, Meng X, Yang H
Cell Immunol · 2026 · PMID 41275570 · Publisher ↗
BACKGROUND: Tumor-derived exosomes play a critical role in facilitating intercellular communication between cancer cells and tumor-associated macrophages (TAMs). Nevertheless, the precise molecular mechanisms underlying...
BACKGROUND: Tumor-derived exosomes play a critical role in facilitating intercellular communication between cancer cells and tumor-associated macrophages (TAMs). Nevertheless, the precise molecular mechanisms underlying exosome-mediated interactions specifically in ovarian cancer remain incompletely elucidated. METHODS: TAMs were treated with exosomes isolated from clinical ovarian cancer specimens. Macrophage polarization was assessed using qRT-PCR, and western blot analysis. RNA sequencing was employed to identify key genes within the exosomes. The malignant phenotype of ovarian cancer cells was evaluated through cell counting kit-8 (CCK-8), Transwell assay, and wound-healing assays. RESULTS: Our findings showed that exosomes derived from both early and late-stage malignant ovarian cancer tissues induced the upregulation of all M2 macrophage markers and the downregulation of M1 markers. RNA sequencing analysis identified thrombospondin-1 (THBS1) as a potential pivotal gene influencing exosome-regulated TAM polarization. THBS1 knockdown within exosomes inhibited the polarization of TAMs toward the M2 phenotype and concurrently decreased transforming growth factor beta induced (TGFBI) expression in macrophages. Notably, TGFBI knockdown in TAM reversed the M2 polarization induced by ovarian cancer cells-derived exosomes. In vivo, ovarian cancer cell-derived exosomes facilitate cancer progression, concomitantly increasing the polarization of M2 macrophages and upregulating THBS1 and TGFBI expression within tumor tissues. CONCLUSION: THBS1, carried by ovarian cancer-derived exosomes, promotes M2 polarization of TAMs by modulating TGFBI expression. The subsequent M2 polarization of TAMs contributes to the establishment of an immunosuppressive tumor microenvironment, thereby facilitating disease progression. Consequently, targeting the exosome-mediated signaling axis between cancer cells and macrophages represents a promising avenue for developing novel therapeutic interventions.
The discovery of regulatory T cells: a paradigm shift in immunology.
Fillatreau S, Hao Y
Cell Immunol · 2026 Jan · PMID 41271530 · Publisher ↗
The immune system is conventionally viewed as an army of fighters present naturally in an inactive state, ready to react to microbial invasion. Activation follows the detection of microbial molecules either by innate rec...
The immune system is conventionally viewed as an army of fighters present naturally in an inactive state, ready to react to microbial invasion. Activation follows the detection of microbial molecules either by innate receptors, which are broadly expressed across cell types, or by antigen-specific receptors - the T cell receptor (TCR) and B cell receptor (BCR) - exclusively found on T and B lymphocytes, respectively. Previously to the discovery of regulatory T cells (Tregs), the induction of immune responses was thought to be controlled exclusively by the provision of activation signals coming from "outside" of the immune system. The discovery of regulatory T cells (Tregs) revealed a radically different mode of immune control. It emphasized immune activation as the default phenomenon at steady state, underlining suppression as essential to maintain immune homeostasis. Under this new view, the induction of immune response can proceed without external signal, upon the removal of key immune breaks internal to the immune system and embodied by Tregs. It fundamentally transformed our understanding of immune regulation and opened new therapeutic avenues for diseases ranging from autoimmunity to cancer. The immense impact of this work was rewarded this year by the attribution of the Nobel prize of Physiology and Medicine to Prof. Shimon Sakaguchi, Prof. Mary E. Brunkow, and Prof. Fred Ramsdell. In this article, we outline the scientific context of these discoveries in the 1990s, and discuss their impact for our understanding of the immune system and the development of novel therapies.
Evaluating the impact of using bone marrow-derived macrophages to turn early tumor sites into hot early tumor sites.
Finn J, Kessler E, Lass M … +2 more , Oviedo-Bermudez E, Kurt RA
Cell Immunol · 2025 Dec · PMID 41223817 · Publisher ↗
The impact of transforming an early tumor site into a hot early tumor site was evaluated using bone marrow-derived macrophages (BMDM) activated with IFN-γ and sCD40L in combination with Toll-like receptor (TLR) agonists...
The impact of transforming an early tumor site into a hot early tumor site was evaluated using bone marrow-derived macrophages (BMDM) activated with IFN-γ and sCD40L in combination with Toll-like receptor (TLR) agonists (lipopolysaccharide (LPS), flagellin or R848). Not surprisingly, analysis of the activated BMDM revealed characteristics often ascribed to anti-tumor (M1) macrophages with production of nitrite and IL-12, as well as expression of Il-1b, Il-6, Tnf-a, Il-18, Ccl5, Cxcl9, Cxcl10, and Cxcl11. All treatments also led to a significant increase in MHC Class II or CD80 expression, but only BMDM activated with IFN-γ and LPS showed a significant increase in both MHC Class II and CD80 expression. Delivering these BMDM to early tumor sites slowed progression of three murine mammary carcinoma models (EMT6, 168, 4 T1). Depletion studies revealed that the anti-tumor activity was dependent upon CD8 T cells and NK cells suggesting that expression of Ccl5, Cxcl9, Cxcl10, and/or Cxcl11 may be important for the in vivo function of the BMDM. Additionally, inhibiting G protein coupled receptor (GPCR) signaling in the BMDM ablated the anti-tumor activity suggesting that the anti-tumor activity may be dependent on the migratory ability of the BMDM. Collectively, these data show that creating hot early tumor sites by delivering anti-tumor BMDM can impact tumor growth by eliciting CD8 T cells and NK cells, and that BMDM anti-tumor activity depends on GPCR-mediated signaling.
The inflammatory effects of a repeated exposure of human macrophages to PM from house dust-SRM 2585 are partially reversible and disrupt the LPS/CD14 signaling pathways.
Marie L, Laura M, Ivannah P … +2 more , Véronique A, Valérie L
Cell Immunol · 2025 Dec · PMID 41205495 · Publisher ↗
OBJECTIVES: To evaluate whether repeated exposures to house dust PM, used at nontoxic concentrations, activate human macrophages after one- and seven-days post-treatment, and whether such PM exposure may alter their resp...
OBJECTIVES: To evaluate whether repeated exposures to house dust PM, used at nontoxic concentrations, activate human macrophages after one- and seven-days post-treatment, and whether such PM exposure may alter their response to LPS. METHODS: Human monocyte-derived macrophages (MDMs) were repeatedly (4 consecutive days) exposed to 1 and 10 μg/cm house dust PM fraction of SRM 2585®. MDM phenotype and functions were evaluated by flow cytometry and ELISA one- and seven-days after the last PM exposure with or without LPS priming during the last 24 h of exposure. RESULTS: PM used at non cytotoxic concentrations induced a pro-inflammatory phenotype characterized by an increased expression of M1 macrophagic markers (CD40, CD80, CD86) and pro-inflammatory cytokines (IL-6, IL-8, TNFα) and a decreased expression of M2 macrophagic markers (CD163, CD204) and of the anti-inflammatory cytokine IL-10, however depending of post-exposure time and the concentration. PM-induced polarization profile of MDM was reversible when they were exposed to 1 μg/cm but not to 10 μg/cm. PM-primed MDMs and then exposed to LPS showed a pro-inflammatory phenotype characterized by altered secretion of IL-8 and IL-10, a decreased expression of CD14, scavenger receptors (SR)-A1 and interferon responsive genes (CXCL9/10, ISG15) and a decrease of endocytosis and phagocytosis of bacteria. CONCLUSIONS: Repeated exposures, even to low concentration of house dust PM, primed MDMs to a pro-inflammatory phenotype that is only partly reversible seven days post-exposure. The altered response of PM-pre-exposed MDMs to LPS might be due to, at least in part, impaired endocytosis crucial for the TLR4/CD14 pathway.
Immunomodulatory effects of mesenchymal stromal cell secretome accelerate repair in a sickle cell disease wound model.
Silveira BM, Ribeiro TO, Freire SM … +6 more , Costa B, Maffili VV, Gonçalves MS, Sogayar M, Nascimento RJM, Fortuna V
Cell Immunol · 2025 Dec · PMID 41202405 · Publisher ↗
Chronic leg ulcers (CLUs) are a debilitating complication of sickle cell disease (SCD), driven by persistent inflammation, immune dysregulation, and vascular dysfunction. Current therapies fail to correct the hostile imm...
Chronic leg ulcers (CLUs) are a debilitating complication of sickle cell disease (SCD), driven by persistent inflammation, immune dysregulation, and vascular dysfunction. Current therapies fail to correct the hostile immune microenvironment that impairs repair. Here, we investigated the therapeutic potential of the adipose-derived mesenchymal stromal cell (ASC) secretome as a cell-free immunomodulatory approach in a preclinical SCD wound model. Full-thickness excisional wounds were induced in Townes HbSS mice and treated topically with ASC secretome or vehicle control. Treatment accelerated wound closure, enhanced re-epithelialization, and reduced inflammatory infiltrates. Histology revealed advanced collagen deposition and matrix organization, while immunofluorescence demonstrated increased CD31, α-SMA, and SM22 expression, indicating neovascularization and perivascular maturation. Gene expression profiling showed early upregulation of IL-10, TGF-β, and ARG1 and later downregulation of TNF, IL-1β, and NOS2, reflecting a shift toward a reparative immune milieu. Increased F4/80 macrophages together with elevated CD31 vascular markers were consistent with immune-vascular interactions. Collectively, these findings demonstrate that ASC secretome restores immune balance, supports vascular integrity, and promotes tissue regeneration in SCD-associated chronic wounds. This study provides preclinical evidence for ASC secretome as a promising, scalable, and cell-free immunomodulatory therapy for refractory chronic wounds.
Mesenchymal stromal cells relieved systemic lupus erythematosus via CCL2 dependent macrophage polarization.
Wen X, Yao G, Zhou Y … +2 more , Liu S, Sun L
Cell Immunol · 2025 Dec · PMID 41187528 · Publisher ↗
Systemic lupus erythematosus (SLE) was an autoimmune disease leading to high morbidity and mortality without effective and low-side effect conventional drugs. Our previous clinical studies demonstrated umbilical cord der...
Systemic lupus erythematosus (SLE) was an autoimmune disease leading to high morbidity and mortality without effective and low-side effect conventional drugs. Our previous clinical studies demonstrated umbilical cord derived mesenchymal stromal cells (MSCs) were a safe and effective treatment, but its therapeutic mechanism is still unclear. In this study, we first observed clinical used MSCs exhibited higher CCL2 expression than primary and aged MSCs, and abnormal bone marrow derived MSC (BM-MSC) from SLE patients performed decreased CCL2 expression compared to healthy control. Then, we constructed CCL2-deficient MSCs, and found the immunosuppressive activity of CCL2-deficient MSCs was impaired in the peripheral blood mononuclear cell (PBMC) inhibitory assay in vitro. CCL2-deficient MSCs also failed to relieve SLE in MRL/lpr and pristine-induced mice. To further explore the role of CCL2 in MSC therapy, we performed transcriptomic profiling of CCL2-deficient MSCs and MSCs, and identified the differential expressed genes were related to chemotaxis, including monocyte chemotaxis. Subsequently, we found that MSCs restored the imbalance in M1/M2 macrophage polarization via CCL2 in vitro. These findings provided valuable insight for investigating the therapeutic mechanism of MSC on SLE.
Differential heterologous immunological effects induced by ChAdOx1-S and BNT162b2 COVID-19 vaccines.
Dulfer EA, Geckin B, Zoodsma M … +7 more , Helder LS, Li W, van Crevel R, van der Maat JS, Li Y, Domínguez-Andrés J, Netea MG
Cell Immunol · 2025 Dec · PMID 41151391 · Publisher ↗
BACKGROUND: The mRNA- and adenovirus-based COVID-19 vaccines may induce different heterologous effects on non-COVID morbidity. We aimed to investigate immunological mechanisms that may account for these differences. METH...
BACKGROUND: The mRNA- and adenovirus-based COVID-19 vaccines may induce different heterologous effects on non-COVID morbidity. We aimed to investigate immunological mechanisms that may account for these differences. METHODS: We selected a subgroup of individuals from the TACTIC trial who had completed their COVID-19 vaccination scheme before the introduction of a BNT162b2 booster vaccine. Transcriptional activity, distribution of cell types and cytokine secretion were compared between those who were originally vaccinated with the adenovirus vaccine ChAdOx1-S, and those who had received the mRNA vaccine BNT162b2. Additionally, we investigated how these differences evolved after administration of a BNT162b2 booster vaccine. RESULTS: 24 individuals were included in this study, with 15 volunteers (62.5%) having originally received an mRNA vaccine and 9 (37.5%) an adenovirus vector vaccine. We found that 84 gene sets were differentially expressed in PBMCs from the two vaccine groups following ex-vivo secondary stimulation. Although cell populations did not significantly differ, pro-inflammatory cytokine responses to most stimuli were consistently higher in the adenovirus group compared to the mRNA group. These differences decreased after an mRNA booster vaccine. DISCUSSION: Our study findings provide additional support to the hypothesis that mRNA- and adenovirus-based vaccines differ in their broad immunological effects. Specifically, our observation that adenovirus-based vaccination tends to result in higher pro-inflammatory cytokine responses might help explain the difference in the heterologous effects of the two types of vaccines. Knowledge about NSEs is increasingly important for making public health and policy decisions, particularly for vulnerable populations.
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