First-generation vaccine candidates against leishmaniasis, based on chemically or physically inactivated whole parasite, have attracted considerable attention owing to their feasibility, scalability of production, and comparatively low manufacturing costs. Vaccine formulations typically require immunostimulatory compounds to elicit robust cell-mediated immunity. Traditionally, adjuvants have been incorporated into vaccine formulation to augment their immunogenic potential. Recent advances over the past decade have yielded novel adjuvant system capable of stimulating both antibody-mediated and cell-mediated immune pathways. Recent advances in adjuvant development have facilitated the design of several promising vaccine candidates against leishmaniasis. Therefore, in the present study, we tested tomatine (identified as a steroidal glycoalkaloid, a saponin subgroup), for its ability to induce cell-mediated immunity that confer protection against leishmaniasis. Tomatine, a glycoalkaloid based adjuvant, possesses the ability to elicit cytotoxic T-lymphocyte responses. It shows remarkable potential as an effective adjuvant candidate for vaccine applications targeting infectious pathogens. Our results demonstrated that tomatine combined with the first-generation antigen induced durable central (CD44[high]CD62L[high]) and effector (CD44[high]CD62L[low]) memory CD4[+] and CD8[+] T-cell responses in both pre-challenge and post-challenge mice, indicating the development of long-lasting protective cellular immunity. Significant protective immunity was further demonstrated in the vaccinated animals, as evidenced by remarkably declined parasite burden, increased levels of T cells (CD4[+], CD8[+]), IFN-γ, GM-CSF, effector molecules i.e. reactive oxygen species and nitric oxide and heightened NF-kB and iNOS gene expression. Collectively, these findings highlight tomatine as an effective immunomodulatory adjuvant capable of inducing cell-mediated protective immunity against leishmaniasis.

Systemic lupus erythematosus (SLE) exhibits marked clinical and biological heterogeneity that is poorly captured by group-based analyses. Using the MRL/Lpr model, we describe an individual mouse displaying a severe phenotype, and provide a characterization combining clinical assessment, inflammatory profiling, neuroaxonal injury, and targeted metabolomics. Despite severe disease, this animal did not display a globally exaggerated cytokine profile relative to other MRL/Lpr mice, although TNFα and IL-1β ranked among the highest in the cohort. In contrast, plasma neurofilament light chain (NfL) was markedly elevated, and metabolomic profiling revealed pronounced disruptions in urea-cycle intermediates, sulfur amino-acid metabolism and muscle-derived metabolites, together with a broad depletion of circulating amino acids. These observations raise the possibility that, at advanced disease stages, circulating cytokine levels may plateau and lose discriminative capacity, whereas metabolic readouts may retain greater capacity to track disease severity.

Primary biliary cholangitis (PBC) is a chronic autoimmune cholestatic liver disease lacking noninvasive biomarkers that adequately reflect disease status. CD161 is an immunoregulatory molecule expressed on T and NK cells, but its soluble (sCD161) and membrane-bound (mCD161) forms remain poorly characterized in PBC. We measured serum sCD161 and cellular mCD161 in patients with PBC, patients with post-hepatitis B cirrhosis (PHBC), and healthy controls (HCs), and examined CD161 expression in a PBC mouse model. Serum sCD161 was markedly elevated in patients with PBC compared with both patients with PHBC and HCs. It correlated positively with the Mayo score, total bilirubin, direct bilirubin, and red cell distribution width and negatively with apolipoprotein A1, albumin, and platelet count. ROC analysis yielded an AUC of 0.8851, with 80.88% sensitivity and 86.79% specificity. The AUC for sCD161 was numerically higher than that for GGT but slightly lower than that for ALP. In contrast, mCD161 expression was reduced across multiple peripheral T-cell subsets. CD161 mRNA levels remained unchanged, whereas ADAM10/17 inhibition reduced sCD161 release and increased cell-surface mCD161 expression, supporting a role for proteolytic shedding in these reciprocal alterations. Reduced CD161 expression was also observed in T-cell subsets from the liver and spleen of PBC model mice, and multiplex immunofluorescence showed fewer hepatic CD4[+]CXCR5[+]CD161[+] cells. These findings support the potential of sCD161 as an adjunctive biomarker for PBC diagnosis and disease assessment.

B cell activation has traditionally been studied to identify the molecular pathways controlling their differentiation into antibody-producing cells. However, B cells can also regulate immune responses through antibody-independent mechanisms, notably by producing the cytokine interleukin-10 (IL-10). Despite increasing interest in the regulatory functions of B cells, the molecular pathways governing IL-10 expression in activated B cells remain incompletely understood. Many signals involved in general B cell activation contribute to IL-10 induction, suggesting that this response is intrinsically linked to the core machinery driving B cell activation, yet only a small fraction of B cells typically expresses IL-10 upon activation in vitro and in vivo. The distinct fate of activated B cells toward IL-10-producing versus non-producing states may reflect quantitative or qualitative differences in the activating signals they receive. A non-mutually exclusive possibility is that specific pathways, distinct from the core B cell activation program, selectively promote IL-10 expression in a subset of activated B cells. Defining these pathways is important because they could potentially be harnessed to suppress pathological immune responses or, conversely, be targeted to enhance protective immunity against tumors and pathogens. In this review, we examine the signals known to regulate IL-10 expression in B cells in the context of their broader roles in B cell activation and differentiation.

The autoimmune regulator (Aire) gene is essential for the establishment of central tolerance by promoting the ectopic expression of tissue-restricted antigens in medullary thymic epithelial cells (mTECs). Although Aire deficiency impairs negative selection, its impact on thymic architecture, output, and early T cell development remains incompletely understood. Here, we used a murine Aire-deficient model carrying a CRISPR-Cas9-induced deletion within exon 6, disrupting the SAND domain, to investigate the consequences of Aire loss on thymic structure and function. Aire-deficient mice exhibited focal alopecia and marked disorganization of the thymic medulla. T cell receptor excision circle (TREC) analyses revealed altered peripheral TREC dynamics and a reduced sj/betaTREC ratio, indicating altered thymic output and impaired intrathymic precursor expansion. Complementary flow-cytometric analysis showed a significant reduction in the proportion of CD4[+]CD8[+] double-positive thymocytes in heterozygous mutants, supporting altered intrathymic maturation. Serum IL-27, IL-28B, and IL-31 were decreased in homozygous mutants, whereas IL-22 and IL-23 remained unchanged. Despite these alterations, TCRVbeta repertoire sequencing revealed no significant differences in rearrangements, clonality, or V/J gene usage. Together, these findings indicate that Aire deficiency disrupts thymic architecture and output, while preserving overall TCR repertoire diversity.

Innate lymphoid cells (ILCs) are innate-like lymphocytes that contribute to tissue homeostasis, barrier immunity, inflammation, and host defense. In metabolic syndrome (MetS), a condition estimated to affect >1.5 billion adults worldwide, dietary patterns and gut microbial metabolites are increasingly recognized as regulators of immune and metabolic dysfunction [1-8]. This review critically summarizes mainly experimental and preclinical evidence, with selected human observations where available, linking dietary components, gut microbiota-derived metabolites, and ILC subsets to obesity, insulin resistance, type 2 diabetes mellitus (T2DM), and related metabolic complications. Current evidence suggests that dietary fibers, short-chain fatty acids, lipids, vitamins, and fermented foods can modulate ILC1, ILC2, and ILC3 responses in a context-dependent manner. However, most mechanistic data derive from mouse models, and direct translation to human MetS remains limited. Through integrating diet-microbiota interactions, ILC subset biology, and metabolic inflammation, this review highlights candidate pathways and biomarkers that may guide future therapeutic studies rather than established clinical interventions.

Secondary immunodeficiency or immunoparesis is an acquired impairment of the immune system which is a recognised feature of multiple myeloma (MM). Although classically described as a reduced production of polyclonal immunoglobulins, MM induces global immune dysfunction with defects in innate immune and T cell effector function. Immunoparesis can be detected in premalignant states, including monoclonal gammopathy of uncertain significance. Patients with immunoparesis have a poorer prognosis and present with severe, recurrent infection, which is associated with increased morbidity and mortality especially in the first 3 months following diagnosis, with relapse or progression and with the use of novel therapeutics. Bacterial infections, and specifically pneumonia, are the commonest presentation although there are increased risks of both viral reactivation and invasive fungal infection. Management of immunoparesis in MM includes the use of antimicrobial prophylaxis, and immunoglobulin replacement therapy particularly during high-risk periods. Although vaccination against encapsulated organisms, reactivation viruses, and circulating seasonal viruses is recommended, the response in MM may be suboptimal.

Oncolytic virotherapy represents a promising frontier in cancer immunotherapy, leveraging the ability of oncolytic viruses (OVs) to selectively replicate within tumour cells and induce antitumour immunity. In this review, we focus on the clinical development of oncolytic poxviruses and propose that understanding fundamental mechanisms of poxvirus-induced cell death can inform rational clinical development strategies that may avoid challenges and improve outcomes in viral immunotherapy. We discuss the development of Olvimulogene nanivacirepvec (Olvi-Vec), Pexastimogene devacirepvec (Pexa-Vec), and other candidates; the basic biology of poxviruses; their manipulation of host antiviral defences; and the pathways of regulated cell death they can induce, including apoptosis, necroptosis, pyroptosis, and ferroptosis. We examine the potential for optimising oncolysis through targeted genetic modification and combination therapy, with the aim of enhancing the immunogenicity of cell death to overcome the immunosuppressive tumour microenvironment and to enhance adaptive antitumour immune responses.