Plasmacytoid dendritic cells (PDCs) represent a crucial bridge between innate and adaptive immunity as they can recognise viruses and viral-infected cells, secrete type I interferon and prime naive T-cell responses. Like naive T cells, PDCs express CD62L, an essential molecule involved in the trans-endothelial migration process, and are supposed to travel directly from blood to lymph nodes to prime naive T cells. We developed a therapeutic PDC line model (PDC*line) derived from a patient with blastic PDC neoplasm, and showing high antigen-presentation capacities. PDC*line-based vaccine was tested in clinical trials in melanoma and lung cancer. Efficient specific T lymphocyte priming was observed suggesting the efficient migration of injected PDC*line-based vaccine to lymph nodes. Here, we investigated the mechanisms involved in this migration and its regulation. In humanised mice, our results demonstrated the efficient migration of the PDC-based vaccine from blood to lymph nodes and its capacity to prime naive T cells. The expression of CD62L was evaluated following irradiation, which was mandatory in the vaccine manufacturing step and possibly important for its efficacy. CD62L was rapidly shed after irradiation of PDC*line cells and primary PDCs but not of NK-T cells, demonstrating the cell specificity of the mechanism. Our results show that p38 MAP kinase, known to be activated in response to irradiation and ADAM17 metalloprotease are involved in the rapid CD62L shedding. This new pathway could participate to the regulation PDC transmigration through High Endothelial Venules and homing to secondary lymphoid organs in cellular stress conditions.
Despite significant advancements in the oncology field, lung cancer remains the leading cause of cancer-related mortality worldwide. A key contributor to the increased mortality rate is the resistance exhibited by cancer cells to standard anticancer treatments, particularly in advanced stages of the disease. Evidence indicates that chronic inflammation within the tumour microenvironment (TME) promotes tumorigenesis and contributes to resistance to immunotherapy, radiotherapy and chemotherapy. Notably, the overexpression of the cytokine interleukin-6 (IL-6) has been documented in various tumours, including lung cancer. Both tumour-associated fibroblasts (TAFs) and tumour cells constitute the predominant sources of secreted IL-6 within the TME. Various research has elucidated the role of IL-6 and its signalling pathways in facilitating therapeutic resistance, metastasis and tumour progression in lung cancer. Consequently, targeting IL-6 and/or its receptor, in conjunction with other effective anticancer treatments, represents an ideal therapeutic technique for lung cancer management. This review aims to synthesize recent evidence on the function of the IL-6/IL-6R signalling pathway in lung cancer, with a focus on its role in therapy resistance, prognosis and tumour progression, on the basis of clinical and preclinical studies.
Acute ischemic stroke is accompanied by marked peripheral and central immune imbalance, in which disruption of the Th17/Treg axis is considered an important driver of aggravated neuroinflammation and secondary injury, yet the upstream regulatory pathways amenable to intervention remain unclear. We hypothesised that the probiotic Akkermansia muciniphila (AKK) could be linked to post-stroke immune remodelling and neuroprotection by influencing intestinal epithelial signalling. Using a tMCAO mouse model combined with AKK intervention, SIRT1 inhibition, IL-17-deficient conditions, and IL-17 neutralisation/rescue experiments, we systematically assessed intestinal barrier integrity, peripheral and central immune responses, and neurological injury, together with single-cell transcriptomic and ATAC-seq analyses of the Th17/Treg axis. Complementary human and murine intestinal epithelial-T cell co-culture systems and a neuronal OGD model were used for functional mechanistic assessment. AKK was associated with activation of AMPK/SIRT1 signalling, decreased Th17 proportions, increased Treg levels, suppression of IL-17-associated inflammatory responses, and enhancement of IL-10 signalling, thereby improving systemic and intracerebral inflammatory environments. In the neuronal OGD model, IL-17 neutralisation alone provided partial protection, combined AKK and IL-17 blockade further enhanced neuroprotection, and recombinant IL-17 rescue attenuated, but did not fully define, the protective effects of AKK. AKK also protected intestinal barrier integrity, reduced infarct volume, and improved neurological function. Together, these findings support a contributory gut epithelial AMPK/SIRT1-associated immunoregulatory network in which AKK is linked to Th17/Treg immune remodelling and reduced post-stroke neuroinflammation through the gut-immune-brain axis, while IL-17 signalling appears to represent one important component rather than an exclusive pathway.
Multiple myeloma remains incurable despite therapeutic advances. Longitudinal profiling of bone marrow and peripheral blood by Chander et al. reveals selective persistence of malignant plasma cell states, compartment-specific immune remodeling, incomplete humoral recovery after autologous stem cell transplantation, and divergent vaccine responses.
Peripheral T cell profiles reflect antitumour immunity, yet systemic immune shifts often remain confounded by demographic factors. This study aimed to delineate true tumour-driven T cell alterations in lung cancer. We analysed peripheral blood from 121 lung cancer patients and strictly age- and sex-matched healthy controls using multiparametric flow cytometry, corroborated by human lung cancer spatial transcriptomics (ST). Following demographic standardisation, patients exhibited a systemic T cell priming blockade, characterised by significantly accumulated naïve T cells and depleted effector memory T cells (CD4+ p < 0.01; CD8+ p < 0.0001). Conversely, Th17.1 cells and immune checkpoints (e.g., PD-1, CTLA-4) were robustly elevated. Crucially, ST validated a striking intratumoural spatial accumulation of Th17.1 cells. We conclude that the peripheral expansion of Th17.1 cells is a genuine tumour-driven event that faithfully mirrors local tumour microenvironment remodelling and potential Tertiary Lymphoid Structure (TLS) neogenesis. This positions peripheral Th17.1 profiling as a valuable, noninvasive biomarker for evaluating systemic immunosuppression and guiding personalised immunotherapy.
Metastasis is an inefficient cellular process in which most disseminated tumor cells fail to form secondary lesions in distant tissues due to hostile conditions, such as protective immune surveillance. The few cells that survive these threats can seed subclinical metastatic lesions, known as micrometastases, which are the least-known stage of the metastatic cascade. In this study, we review micrometastasis immunobiology, which differs from that of larger, clinically manifested metastasis. Key mechanisms such as epithelial-to-mesenchymal transition, stemness, dormancy, and immune evasion shape this bottleneck of metastasis, determining long-term disease evolution, therapy responses, and patient outcomes. Understanding micrometastasis immunology may reveal therapeutic opportunities to fully eradicate disseminated cells. Thus, we discuss emerging time-tailored immunopreventive strategies to intercept the progression to overt metastasis.
Cytokines are key messenger molecules that bridge the nervous and immune systems through a bidirectional signalling network. Beyond their roles in development and homeostasis, neuronal cytokine sensing allows the central nervous system (CNS) to detect early immune perturbations, such as those triggered by emerging infections. Because neurons are postmitotic cells, rapid antipathogen responses are essential to prevent cell loss and ensure host survival. However, when CNS inflammation persists, as in chronic neuroinflammatory conditions such as multiple sclerosis or in age-associated inflammageing, cytokine signalling can become maladaptive and drive disease pathology. This review examines recent findings and emerging tools for studying how CNS neurons sense and respond to cytokines in both health and disease.
Mitochondrial complex II, succinate dehydrogenase (SDH), links the tricarboxylic acid cycle to the electron transport chain by oxidizing succinate to fumarate and reducing ubiquinone. This unusual position gives Complex II control over bioenergetics, redox state, succinate signaling, and chromatin regulation. In immune cells, Complex II regulates macrophage responses via the succinate-hypoxia-inducible factor-1α-IL-1β axis, T-cell proliferation, lineage commitment, and cytotoxicity. In target tissues of an aberrant immune attack, such as the intestinal epithelium and stem-cell compartments, SDHA loss lowers tissue tolerance, promotes inflammatory memory through succinate-driven epigenetic reprogramming, and amplifies immune-mediated injury. In tumors, SDH loss increases antigen presentation and their susceptibility to T-cell killing. Complex II, therefore, regulates immunopathology through its actions within both attacking immune cells and injured target tissues.
Transmembrane activator and calcium-modulator and cyclophilin-ligand interactor (TACI), encoded by TNFRSF13B, plays a central role in B cell maturation and antibody responses through its interactions with BAFF and APRIL, with variants being linked to common variable immunodeficiency (CVID) and selective IgA deficiency. To characterise the clinical, immunological and genetic spectrum of these individuals, we recruited 30 participants (21 patients and nine family members) and classified patients into Group 1 (n = 16), carrying only TACI variants and Group 2 (n = 5), carrying both an IEI-related variant and an additional TACI variant. With a male/female ratio of 12/9, the median age was 2 years at symptom onset and 14 years at genetic diagnosis. Common clinical manifestations included recurrent infections (90%), autoimmune/inflammatory features (62%) and lymphoproliferation (57%). Twelve distinct TNFRSF13B mutations were identified, predominantly clustering in the cysteine-rich domain 2 (CRD2), with Cys104Arg being the most frequent (57%) variant. Immunophenotyping revealed decreased switched-memory and marginal zone B cells, reduced naïve CD4+ T cells and increased effector memory subsets. Notably, clinical and laboratory features overlapped between Groups 1 and 2, as well as between monoallelic and biallelic TNFRSF13B variant carriers. Patients with TNFRSF13B variants display broad phenotypic heterogeneity ranging from asymptomatic carriage to CVID and combined immunodeficiency phenotypes. Given the high polymorphism ratio and incomplete penetrance observed, TACI acts as both a genetic modifier and a monogenic disease-causing gene in this cohort, suggesting that coexisting genetic variants and exposomal factors likely determine the clinical expression and disease severity.
Natural killer (NK) cells are effectors of innate antitumor immunity, yet their therapeutic potential in solid tumors remains largely unrealized. Breast cancer exemplifies this paradox: NK cells are present in circulation and detectable within tumors, but their cytotoxic activity is limited. Recent advances in single-cell and spatial profiling reveal that NK-cell failure in breast cancer does not result from simple immune absence but from multilayered constraints imposed by the tumor ecosystem. Soluble mediators, metabolic pressures, stromal architecture, and suppressive immune networks reprogram NK-cell identity and uncouple activation from cytotoxicity. Understanding how these constraints shape NK-cell states reframes breast cancer as a model of innate immune dysfunction and highlights new opportunities to reestablish NK-cell function through immunotherapies.
Traditionally considered immune-privileged, the central nervous system (CNS) is now recognised as immunologically dynamic, with the meninges serving as a key interface for immune surveillance and neuroimmune communication. Recent advances support the emerging concept of a gut-meningeal immune axis, wherein the gut microbiota may influence meningeal immunity, through the recruitment of gut-educated immune cells and other microbiota-dependent signals, although the mechanisms involved remain incompletely understood. Notably, the neonatal period represents a critical window of immune and microbial development, during which dysbiosis can disrupt microglia maturation, cytokine balance, and long-term neuroimmune resilience. Here, we review the structural and immunological properties of the meninges, the mechanisms potentially linking the gut microbiota to meningeal immunity, and the role of this emerging axis in neuroinflammatory diseases. We further explore the developmental implications of early-life microbial disturbances and discuss the therapeutic potential of microbiota-targeted interventions to modulate meningeal immunity and mitigate CNS pathology.
Autoimmune and autoinflammatory diseases are characterised by dysregulated immune activation and persistent inflammation, yet effective mechanism-based therapeutic targets remain limited. Proline-serine-threonine phosphatase-interacting protein 2 (PSTPIP2), a membrane-cytoskeleton-associated adaptor protein predominantly expressed in myeloid cells, has emerged as an important endogenous regulator of inflammatory responses. This review summarises the molecular structure, expression pattern and biological functions of PSTPIP2, with particular emphasis on its role in coordinating cytoskeletal remodelling, inflammatory signalling and immune-cell behaviour. We further discuss the major mechanisms through which PSTPIP2 regulates disease progression, including suppression of IL-1β maturation, inhibition of NF-κB and ERK signalling, modulation of macrophage polarisation and control of osteoclast-associated bone remodelling. In addition, recent advances in understanding the involvement of PSTPIP2 in chronic multifocal osteomyelitis, rheumatoid arthritis, SAPHO syndrome and bullous pemphigoid are reviewed, together with evidence from PSTPIP2-deficient models that has provided important mechanistic and translational insights. Finally, the potential value of PSTPIP2 as a biomarker and therapeutic target is highlighted. Overall, PSTPIP2 represents a critical immunoregulatory node linking cytoskeletal organisation to inflammatory control, and further investigation of its molecular functions may facilitate the development of precision therapies for autoimmune and autoinflammatory diseases.
Clostridioides difficile infection (CDI) remains a major cause of antibiotic-associated colitis and is characterized by excessive intestinal inflammation, epithelial barrier disruption and impaired mucosal repair. Although sodium butyrate (NaB), a microbiota-derived short-chain fatty acid, has demonstrated anti-inflammatory and barrier-protective properties, the immunological mechanisms underlying its protective effects during CDI remain incompletely understood. In this study, we investigated the role of NaB in regulating macrophage polarization and epithelial repair using murine CDI models, primary bone marrow-derived macrophages, THP-1-derived macrophages, Caco-2 epithelial cells and macrophage-epithelial co-culture systems. NaB treatment significantly alleviated CDI-associated weight loss, colonic shortening, histopathological injury and inflammatory cytokine production while restoring epithelial barrier integrity and tight junction protein expression. Mechanistically, NaB promoted macrophage polarization towards an anti-inflammatory M2 phenotype, characterized by increased CD206 and IL-10 expression and reduced CD86 and IL-1β expression. These immunomodulatory effects were accompanied by suppression of PI3K/Akt/mTOR signalling in both colonic tissues and macrophages. Pharmacological inhibition and activation studies further supported the involvement of this pathway in NaB-mediated macrophage reprogramming. Importantly, conditioned medium from NaB-treated macrophages enhanced epithelial viability, migration and barrier-associated protein expression, whereas IL-10 neutralization partially abolished these protective effects, highlighting a critical role for macrophage-epithelial crosstalk. Collectively, our findings demonstrate that low-dose NaB protects against CDI-induced intestinal injury through coordinated regulation of macrophage polarization and epithelial barrier repair, at least in part via modulation of PI3K/Akt/mTOR signalling. These results identify NaB as a promising host-directed therapeutic strategy for CDI and provide new insights into microbiota-derived metabolite-immune interactions during intestinal inflammation.
Tumour immune evasion frequently involves PD-L1-mediated inhibition of T cell activity, limiting the efficacy of PD1/PD-L1 blockade, particularly in PD-L1-low or immunologically 'cold' tumours. To overcome this limitation, we developed a dual targeting human PD1-CD137L (hPD1-CD137L) fusion protein that blocks PD-L1-PD1 inhibitory signalling and simultaneously delivers CD137-mediated T cell costimulation. The fusion protein was produced with high purity and demonstrated specific binding to PD-L1-expressing tumour cells and CD137-positive T cells. The hPD1-CD137L retained a stable multimeric structure under acidic conditions and during prolonged storage, supporting its suitability for systemic administration and activity within the tumour microenvironment. Functionally, hPD1-CD137L enhanced T cell activation, as evidenced by increased NF-κB signalling and activation marker expression, and promoted robust tumour cell cytolysis in both 2D and 3D co-culture systems. Anti-tumour activity was observed across multiple tumour models with varying PD-L1 expression, including nasopharyngeal carcinoma (NPC), rhabdomyosarcoma, lung carcinoma and patient-derived colorectal cancer organoids. Notably, hPD1-CD137L enhanced cytolysis of C666 NPC cells by patient-derived tumour-infiltrating lymphocytes at low effector-to-target ratios, and was more potent than a combination of an anti-PD-1 antibody and a CD137 agonist. In vivo, PBMC-humanised NSG mice tolerated hPD1-CD137L without significant weight loss, systemic inflammation or survival impact. Subsequent efficacy study in PBMC-humanised, Rd18 rhabdomyosarcoma-engrafted or C666 nasopharyngeal carcinoma-engrafted NSG mice showed tumour growth suppression without overt toxicity. This study validates a human PD1-CD137L fusion protein as a potent drug candidate for cancer immunotherapy.
Immune surveillance of the central nervous system (CNS) is regulated by the brain barriers. Antigen presentation at the blood-brain barrier (BBB) has been proposed to promote antigen-specific T-cell entry into the CNS, largely based on in vitro studies. Recent in vivo and transcriptomic studies call for a reassessment of this concept. In healthy mouse and human CNS endothelium, major histocompatibility complex (MHC) class I expression is low, and MHC class II is minimal to absent. During neuroinflammation, brain microvascular endothelial cells (BMECs) can acquire antigen-presenting features, predominantly in the context of strong or prolonged inflammation. We propose that BMEC antigen presentation amplifies vascular pathology rather than initiating CNS T-cell entry during immune surveillance or disease.
Myo1g, a short-tail class I myosin, has been extensively studied for its roles in cellular adhesion, migration, cytokine secretion and receptor recycling in T and B lymphocytes. However, its involvement in other immune cell populations, particularly natural killer (NK) cells, remains an open question in immunology. NKR-P1C is a type II integral membrane glycoprotein with a C-type lectin domain; it also plays roles in NK cell activation and differentiation, IFN-γ production, cytotoxic granule release. The expression of Myo1f and Myo1g mRNA in NK cells was previously found in the RIKEN database (https://gexc.riken.jp/). Thus, the present study began by confirming the presence of Myo1g protein in lysates from splenic NK cells of wild-type (WT) mice. Subsequently, it was found that mice deficient in Myo1g (Myo1g-/-) exhibited decreased frequency and absolute numbers of NK cells (defined as CD3-, CD19- and NKR-P1C+ lymphocytes) in the bone marrow, blood and spleen. Then, NK cell development was evaluated (CD122, CD49b and NKp46), demonstrating that the absence of Myo1g does not affect overall NK cell generation but does influence NKR-P1C expression. A functional analysis revealed reduced degranulation in NK cells from Myo1g-/- mice compared to WT controls. These findings were corroborated using purified NK cells, which demonstrated that NK cells from Myo1g-/- deficient mice exhibit reduced cytotoxicity. Collectively, these results suggest that Myo1g may serve as a potential target for modulating NK cell function and immune responses. To hypothesize potential mechanisms linking Myo1g to NKR-P1C expression and cytotoxicity, it is possible that Myo1g influences the stability or surface trafficking of NKR-P1C, given its known role in receptor recycling. Additionally, the absence of Myo1g could impair the cytoskeletal reorganisation required for NK cell function, affecting the formation of immunological synapses and the subsequent degranulation process.
The myeloid differentiation primary response protein 88 (MyD88) family of Toll/interleukin-1 receptor (TIR) domain-containing adaptor proteins constitutes a central signalling hub that integrates innate immune sensing with tissue-specific stress responses. This family comprises five mammalian members: MyD88, TIRAP/MAL, TRIF/TICAM-1, TRAM/TICAM-2 and SARM1 (also known as MyD88-1 through MyD88-5). While these adaptors are classically defined by their roles in immune and haematopoietic cells, accumulating genetic and mechanistic evidence demonstrates critical, cell-intrinsic functions in non-immune tissues. Canonical MyD88 signalling assembles IRAK-containing complexes to activate NF-κB and MAPK pathways, whereas TIRAP and TRAM function as sorting adaptors that impose spatial and receptor specificity. TRIF mediates MyD88-independent interferon programs downstream of Toll-like receptor (TLR)-3 and internalised TLR-4. Beyond immunity, MyD88-family signalling regulates epithelial barrier integrity, hepatic metabolic homeostasis, skeletal muscle metabolism and atrophy, endothelial permeability, renal injury responses and neuronal degeneration. Notably, SARM1 represents a functionally divergent family member whose TIR domain acts as an intrinsic NAD+ hydrolase driving axonal degeneration. Here, we synthesise structural, genetic and cell-specific studies to highlight how compartmentalised adaptor usage and domain-specific mechanisms generate context-dependent signalling outcomes across immune and non-immune tissues. These insights redefine MyD88-family adaptors as modular regulators of tissue physiology and disease, with implications for targeted therapeutic intervention.
