Tuberculosis (TB) continues to pose a significant global health threat, highlighting the urgent need for the development of rapid, precise, and accessible diagnostic tools to effectively manage its transmission. Conventional diagnostic techniques, such as sputum microscopy and culture-based assays, face several drawbacks, including lengthy processing times, limited sensitivity, and the requirement for specialized laboratory facilities. In this landscape, electrochemical biosensors have emerged as promising alternatives, offering improved sensitivity, specificity, and rapid detection capabilities. This review presents a thorough overview of recent advancements in the development and application of innovative electrochemical biosensors for TB detection. It explores the integration of nanomaterials such as graphene, gold nanoparticles, and carbon nanotubes, focusing on their contributions to enhanced sensor performance in terms of signal amplification and biorecognition efficacy. By synthesizing current research and technological developments, this review emphasizes the considerable potential of electrochemical biosensors to transform TB diagnostics, ultimately assisting in better disease management and control strategies worldwide.

Adaptive immunity towards self-antigens (autoimmunity) and intestinal commensal microbiota is a key feature of inflammatory bowel disease (IBD). Considering mucosal adaptive immunity from a holobiont perspective, where the host and its microbiome form a single physiological unit, emphasises the challenge of avoiding damaging responses to self-antigen and symbiotic microbial communities in the gut while protecting against potential pathogens. Intestinal tolerance mechanisms prevent maladaptive T and B cell responses to microbial, environmental, and self-antigens, which drive inflammation. We discuss the spectrum of antimicrobial and autoantibody responses and highlight mechanisms by which common IBD-associated adaptive immune responses contribute to disease.

Unconventional T (UC T) cells, including invariant natural killer T (iNKT) cells, mucosal-associated invariant T (MAIT) cells, γδ T cells, and double-negative (DN) T cells, are key players in immune surveillance and response due to their properties combining innate-like and adaptive-like features. These cells are widely present in mucosal tissues, where they can rapidly respond to infections and tumor-associated changes. In fact, UC T cells can have both pro- and anti-tumoral effects, with their activity influenced by factors such as microbial composition and the tumor microenvironment. In particular, intratumoral microbiota significantly impacts the development, function, and activation of UC T cells, influencing cytokine production and shaping the immune response in various cancers. The complex crosstalk between UC T cells and the surrounding factors is discussed in this review, with a focus on how these cells might be interesting candidates to explore and exploit as anticancer therapeutic agents. However, the great potential of UC T cells, not only demonstrated in the context of adoptive cell transfer, but also enhanced through techniques of engineering, is still flanked by different challenges, like the immunosuppressive tumor microenvironment and heterogeneity of target molecules associated with some specific categories of tumors, like gastrointestinal cancers.

The activation and polarization of T cells play a crucial role in atherosclerosis and dictate athero-inflammation. The epigenetic enzyme EZH2 (enhancer of zeste homolog 2) mediates the H3K27me3 (trimethylation of histone H3 lysine 27) and is pivotal in controlling T cell responses.

To detail the role of T cell EZH2 in atherosclerosis, we used human carotid endarterectomy specimens to reveal plaque expression and geography of EZH2. Atherosclerosis-prone Apoe (apolipoprotein E)-deficient mice with CD (cluster of differentiation) 4+ or CD8+ T cell-specific Ezh2 deletion (Ezh2cd4-knockout [KO], Ezh2cd8-KO) were analyzed to unravel the role of T cell Ezh2 in atherosclerosis and T cell-associated immune status.

EZH2 expression is elevated in advanced human atherosclerotic plaques and primarily expressed in the T cell nucleus, suggesting the importance of canonical EZH2 function in atherosclerosis. Ezh2cd4-KO, but not Ezh2cd8-KO, mice showed reduced atherosclerosis with fewer advanced plaques, which contained less collagen and macrophages, indicating that Ezh2 in CD4+ T cells drives atherosclerosis. In-depth analysis of CD4+ T cells of Ezh2cd4-KO mice revealed that absence of Ezh2 results in a type 2 immune response with increased Il-4 (interleukin 4) gene and protein expression in the aorta and lymphoid organs. In vitro, Ezh2-deficient T cells polarized macrophages toward an anti-inflammatory phenotype. Single-cell RNA-sequencing of splenic T cells revealed that Ezh2 deficiency reduced naive, Ccl5+ (C-C motif chemokine ligand 5) and regulatory T cell populations and increased the frequencies of memory T cells and invariant natural killer T (iNKT) cells. Flow cytometric analysis identified a shift toward Th2 (type 2 T helper) effector CD4+ T cells in Ezh2cd4-KO mice and confirmed a profound increase in splenic iNKT cells with increased expression of Plzf (promyelocytic leukemia zinc finger), which is the characteristic marker of the iNKT2 subset. Likewise, Zbtb16 ([zinc finger and BTB domain containing 16], the Plzf-encoding gene) transcripts were elevated in the aorta of Ezh2cd4-KO mice, suggesting an accumulation of iNKT2 cells in the plaque. H3K27me3-chromatin immunoprecipitation followed by quantitative polymerase chain reaction showed that T cell-Ezh2 regulates the transcription of the Il-4 and Zbtb16 genes.

Our study uncovers the importance of T cell EZH2 in human and mouse atherosclerosis. Inhibition of Ezh2 in CD4+ T cells drives type 2 immune responses, resulting in an accumulation of iNKT2 and Th2 cells, memory T cells and anti-inflammatory macrophages that limit the progression of atherosclerosis.

T-cell receptor (TCR) γδ-expressing cells are conserved lymphocytes of innate immunity involved in first-line defense and immune surveillance. TCRγδ recognizes protein/nonprotein ligands without the help of the major histocompatibility complex (MHC), especially via direct binding to protein ligands, which is dependent primarily on the δ chain complementary determining region 3 (CDR3δ). However, the mechanism of protein‒antigen recognition by human γδ TCRs remains poorly defined. We hypothesize that γδ TCRs recognize self-proteins expressed ectopically on the cell membrane that are derived from intracellular components under stress. Here, we mapped 16 intercellular self-proteins among 21,000 proteins with a huProteinChip as putative ligands for Vδ1/Vδ2 TCRs, 13 for Vδ1 TCRs and 3 for Vδ2 TCRs. Functional tests confirmed that ectopic nucleolin (NCL) is a ligand for the Vδ1 TCR, whereas protein-glutamine γ-glutamyltransferase K (TGM1) is a ligand for the Vδ2 TCR. In the context of radiation exposure, the ectopic expression of intracellular proteins on the tumor cell surface is related to the increased antitumor cytotoxicity of γδ T cells both in vitro and in vivo. In conclusion, the recognition of intracellular proteins that are ectopically expressed on somatic cells by human γδ TCRs is a basic interaction mechanism that enables new types of immune pattern recognition and a novel γδ TCR-ligand-based strategy for tumor immunotherapy.

CD1d is an antigen-presenting molecule that presents lipid or glycolipid antigens to iNKT cells, a distinct subset of T lymphocytes characterised by their innate-like properties and restricted use of Vα, Jα and Vβ segments. The CD1d-iNKT axis represents an interesting aspect of the immune system with significant potential for therapeutic interventions against infectious diseases. Upon recognition of lipid antigens, iNKT cells initiate rapid and potent immune responses, releasing a diverse array of cytokines such as IL-4, IL-13, IFN-γ etc. that profoundly influence immune reactions against various pathogens, including bacteria and parasites, bridging innate and adaptive immunity. We identify and describe the key features of lipidic antigens and their derivatives that determine the nature of their antigenicity. Furthermore, modulating CD1d-driven iNKT cell responses by an array of lipid and glycolipid antigens holds promise as adjunctive therapy to existing antimicrobial treatments. Understanding the complexities of the CD1d-iNKT axis and exploiting its therapeutic potential in the case of infectious diseases could lead to innovative immunotherapeutic strategies, ushering in a new era of immunotherapy against pathogenic insults.

Mucosal-associated invariant T (MAIT) cells are evolutionarily conserved T cells that recognize microbial metabolites. They are abundant in humans and conserved during mammalian evolution, which suggests that they have important nonredundant functions. In this article, we discuss the evolutionary conservation of MAIT cells and describe their original developmental process. MAIT cells exert a wide variety of effector functions, from killing infected cells and promoting inflammation to repairing tissues. We provide insights into these functions and discuss how they result from the context of stimulation encountered by MAIT cells in different tissues and pathological settings. We describe how MAIT cell numbers and features are modified in disease states, focusing mainly on in vivo models. Lastly, we discuss emerging strategies to manipulate MAIT cells for therapeutic purposes.

Approximately one-quarter of the global population is estimated to be infected with Mycobacterium tuberculosis. New developments in vaccine design and therapeutics are urgently needed, particularly in the face of multidrug-resistant tuberculosis (TB). In this issue of the JCI, Sakai and colleagues used a multidisciplinary approach to determine that trehalose-6-monomycolate (TMM), a mycobacterial cell wall lipid, serves as a T cell antigen presented by CD1b. CD1b-TMM-specific T cells were characterized by conserved T cell receptor features and were present at elevated frequencies in individuals with active TB disease. These findings highlight the dual role of TMM in stimulating both innate and adaptive immunity and broaden our understanding of CD1-mediated lipid recognition by unconventional T cells.

CD4-CD8- TCRαβ+ (double-negative [DN]) T cells represent a rare T cell population that promotes immunological tolerance through various cytotoxic mechanisms. In mice, autologous transfer of DN T cells has shown protective effects against autoimmune diabetes and graft-versus-host disease. Here, we characterized human DN T cells from people living with type 1 diabetes (PWT1D) and healthy controls. We found that while DN T cells and CD8+ T cells share many similarities, DN T cells are a unique T cell population, both at the transcriptomic and protein levels. We also show that by using various cytokine combinations, human DN T cells can be expanded in vitro up to 1,000-fold (mean >250-fold) and remain functional post-expansion. In addition, we report that DN T cells from PWT1D display a phenotype comparable to that of healthy controls, efficiently expand, and are highly functional. As DN T cells are immunoregulatory and can prevent T1D in various mouse models, these observations suggest that autologous DN T cells may be amenable to therapy for the prevention or treatment of T1D.

Chickens are renowned as a model for embryogenesis but have also been responsible for crucial advances in virology, cancer research and immunology. However, chickens are best known as a major source of animal protein for human nutrition, with roughly 80 billion chickens alive each year supplying meat and eggs, the vast majority part of a global poultry industry. As a result, avian immunology been studied intensively for over 60 years, and it has become clear that a major genetic locus in chickens determining resistance to infectious disease and response to vaccines is the major histocompatibility complex (MHC). Compared to typical mammals, the chicken MHC is compact and simple, with only two classical class I genes. A dominantly-expressed class I gene, BF2, is the major ligand for cytotoxic T lymphocytes (CTLs), while the other locus, BF1, is much less well-expressed, lacking in some MHC haplotypes, and is a ligand for natural killer (NK) cells. Cell surface class I expression in neonatal chicks is far less than in adults, and one possibility is that BF2 is not well-expressed early in ontogeny. A precedent is found for amphibians: the single classical class I molecule is not expressed in tadpoles of Xenopus frogs, although non-polymorphic (and thus non-classical) class I molecules from the XNC locus are expressed, which are recognised for immune defence by non-canonical NKT lymphocytes. Indeed, three waves of different T cells are produced by the Xenopus thymus: in tadpoles, during metamorphosis and finally as adults. Three waves of thymic emigrants are also found for chickens, and reasoning by analogy, it may be that the waves of thymocytes and the expression of class I molecules during ontogeny of chickens are evolutionary relics. As well as scientific interest in the ontogeny of MHC class I expression and appearance of peripheral T cells, there are potential practical implications, given the importance of vaccination in ovo and in day-old chicks for the poultry industry.

Over the past 50 years, the contribution of the immune system has been identified in the development of hypertension and renal injury. Both human and experimental animal models of hypertension have demonstrated that innate and adaptive immune cells, along with their cytokines and chemokines, modulate blood pressure fluctuations and end organ renal damage. Numerous cell types of the innate immune system, specifically monocytes, macrophages, and dendritic cells, present antigenic peptides to T cells, promoting inflammation and the elevation of blood pressure. These T cells and other adaptive immune cells migrate to vascular and tubular cells of the kidney and promote end-organ fibrosis, damage, and ultimately hypertensive injury. Through the development of high-throughput screening, novel renal and immune cell subsets have been identified as possible contributors and regulators of renal injury and hypertension. In this review, we will consider classical immunological cells and their contribution to renal inflammation, and novel cell subsets, including renal stromal cells, that could potentially shed new light on renal injury and hypertension. Finally, we will discuss how interorgan inflammation contributes to the development of hypertension and hypertension-related multiorgan damage, and explore the clinical implications of the immunological components of renal injury and hypertension.

Mucosal-Associated Invariant T (MAIT) cells, which bridge innate and adaptive immunity, have emerged as an important player in viral infections despite their inability to directly recognize viral antigens. This review provides a comprehensive analysis of MAIT cell responses across different viral infections, revealing consistent patterns in their behavior and function. We discuss the dynamics of MAIT cells during various viral infections, including changes in their frequency, activation status, and functional characteristics. Particular attention is given to emerging strategies for MAIT-cell-targeted vaccine development, including the use of MR1 ligands as mucosal adjuvants and the activation of MAIT cells through viral vectors and mRNA vaccines. Current knowledge of MAIT cell biology in viral infections provides promising approaches for harnessing their functions in vaccine development.

Mucosal inflammation is involved in the pathophysiology of immunoglobulin-A nephropathy (IgAN); however, peripheral immune phenotype analyses of patients with IgAN often do not include unconventional T cells, the major subset in mucosal immunity.

We measured serum total IgA, galactose-deficient IgA1 (gd-IgA1), secretory IgA (SIgA), B cell-activating factor (BAFF), and A proliferation-inducing ligand (APRIL) in 66 patients with IgAN and 30 healthy controls (HCs). We also quantified the total IgA and gd-IgA1 in stool supernatant along with the same coated on bacteria. In 35 patients and 14 controls, we performed extensive phenotyping using cytometry by Time-of-Flight (CyTOF) of circulating immune cells, including unconventional T cells (mucosal associated invariant T [MAIT] cells, γδ T, and natural killer [NK] T cells). The results were validated using RNAseq data from a larger cohort of 179 patients with IgAN, 140 patients with minimal change disease, and 91 HCs.

Patients with IgAN had higher circulating levels of total IgA, gd-IgA1, and APRIL, and higher IgA and gd-IgA1-coated gut bacteria than controls, whereas serum levels of SIgA and BAFF did not differ between groups. Patients with IgAN showed more class-switched memory (CSM) and double negative (DN) B cells than controls. MAIT cells and γδ T cells were significantly lower, and CD4-CD8- NK T cells were significantly higher in patients with IgAN than in HCs. We validated the significant decrease in MAIT cells in an independent cohort of patients with IgAN.

The data indicate that patients with IgAN have increased circulating CSM and DN B cells associated with abnormal T cell immunity, involving defects in unconventional T cell frequency. This may suggest putative alterations at mucosal sites because of cell migration leading to altered IgA production.

Tissue-resident immune cells (TRICs) are a highly heterogeneous and plastic subpopulation of immune cells that reside in lymphoid or peripheral tissues without recirculation. These cells are endowed with notably distinct capabilities, setting them apart from their circulating leukocyte counterparts. Many studies demonstrate their complex roles in both health and disease, involving the regulation of homeostasis, protection, and destruction. The advancement of tissue-resolution technologies, such as single-cell sequencing and spatiotemporal omics, provides deeper insights into the cell morphology, characteristic markers, and dynamic transcriptional profiles of TRICs. Currently, the reported TRIC population includes tissue-resident T cells, tissue-resident memory B (BRM) cells, tissue-resident innate lymphocytes, tissue-resident macrophages, tissue-resident neutrophils (TRNs), and tissue-resident mast cells, but unignorably the existence of TRNs is controversial. Previous studies focus on one of them in specific tissues or diseases, however, the origins, developmental trajectories, and intercellular cross-talks of every TRIC type are not fully summarized. In addition, a systemic overview of TRICs in disease progression and the development of parallel therapeutic strategies is lacking. Here, we describe the development and function characteristics of all TRIC types and their major roles in health and diseases. We shed light on how to harness TRICs to offer new therapeutic targets and present burning questions in this field.

Alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) are two major chronic liver diseases worldwide. The triggers for fatty liver can be derived from external sources such as adipose tissue, the gut, personal diet, and genetics, or internal sources, including immune cell responses, lipotoxicity, hepatocyte death, mitochondrial dysfunction, and extracellular vesicles. However, their pathogenesis varies to some extent. This review summarizes various immune mechanisms and therapeutic targets associated with these two types of fatty liver disease. It describes the gut-liver axis and adipose tissue-liver crosstalk, as well as the roles of different immune cells (both innate and adaptive immune cells) in fatty liver disease. Additionally, mitochondrial dysfunction, extracellular vesicles, microRNAs (miRNAs), and gastrointestinal hormones are also related to the pathogenesis of fatty liver. Understanding the pathogenesis of fatty liver and corresponding therapeutic strategies provides a new perspective for developing novel treatments for fatty liver disease.

Foot-and-mouth disease (FMD) causes significant economic losses, prompting vaccination as a primary control strategy. Virus-like particles (VLPs) have emerged as promising candidates for FMD vaccines but require adjuvants to enhance their immunogenicity. In this study, we evaluated the immunogenicity of a VLP-based vaccine with a water-in-oil-in-water (W/O/W) emulsion adjuvant, named WT.

The WT adjuvant was mixed with FMD VLPs to form the VLPs+WT vaccine. The size and stability of the vaccine were analyzed. BALB/c mice were immunized with the VLPs+WT vaccine, and immunological responses were assessed through antibody measurements, cytokine profiling, and gene expression analysis. In addition, splenic lymphocyte proliferation and signaling pathways were examined.

The VLPs+WT vaccine exhibited a homogeneous size of 324.60 ± 2.30 nm and a viscosity of 8.76 mPa·s, indicating good stability. Immunized mice showed steady weight gain and no organ abnormalities. Compared to the VLPs group, the VLPs+WT group induced significantly higher levels of specific antibodies that persisted for 12 weeks, similar to the commercial VLPs+ISA201 vaccine. The VLPs+WT vaccine also enhanced the secretion of Th1-related (IgG2a, IFN-γ) and Th2-related (IgG1, IL-4) molecules. WT stimulated splenic lymphocyte proliferation and differentiation, primarily activating B-cell receptor signaling and phagosome pathways. It also upregulated genes associated with MHC and interferon stimulation while promoting the expression of MyD88, PI3K, AKT, p65, and p-p65 proteins.

These findings suggest that WT is an effective adjuvant for FMD VLP-based vaccines, with potential for improving vaccine efficacy.

Mycobacterium tuberculosis causes human tuberculosis (TB). As mycobacteria are protected by a thick lipid cell wall, humans have developed immune responses against diverse mycobacterial lipids. Most of these immunostimulatory lipids are known as adjuvants acting through innate immune receptors, such as C-type lectin receptors. Although a few mycobacterial lipid antigens activate unconventional T cells, the antigenicity of most adjuvantic lipids is unknown. Here, we identified that trehalose monomycolate (TMM), an abundant mycobacterial adjuvant, activated human T cells bearing a unique αβ T cell receptor (αβTCR). This recognition was restricted by CD1b, a monomorphic antigen-presenting molecule conserved in primates but not mice. Single-cell TCR-RNA-Seq using newly established CD1b-TMM tetramers revealed that TMM-specific T cells were present as CD4+ effector memory T cells in the periphery of uninfected donors but expressed IFN-γ, TNF, and anti-mycobacterial effectors upon TMM stimulation. TMM-specific T cells were detected in cord blood and PBMCs of donors without bacillus Calmette-Guérin vaccination but were expanded in patients with active TB. A cryo-electron microscopy study of CD1b-TMM-TCR complexes revealed unique antigen recognition by conserved features of TCRs, positively charged CDR3α, and long CDR3β regions. These results indicate that humans have a commonly shared and preformed CD4+ T cell subset recognizing a typical mycobacterial adjuvant as an antigen. Furthermore, the dual role of TMM justifies reconsideration of the mechanism of action of adjuvants.

In the context of chronic hepatitis B virus (HBV) infection, the continuous replication of HBV within host hepatocytes is a characteristic feature. Rather than directly causing hepatocyte destruction, this replication leads to immune dysfunction and establishes a state of T-B immune tolerance. Successful clearance of the HBV virus is dependent on the close collaboration between humoral and cellular immunity. Humoral immunity, mediated by B-cell subpopulations, and cellular immunity, dominated by T-cell subpopulations show varying degrees of dysfunction during chronic hepatitis B (CHB). Notably, not all T- and B-cells produce positive immune responses. This review examine the most recent developments in the mutual regulation of T-B cells during chronic HBV infection. Our focus is on the prevailing immunotherapeutic strategies, such as T cell engineering, HBV-related vaccines, PD-1 inhibitors, and Toll-like receptor agonists. While nucleos(t)ide analogues (NUCs) and interferons have notable limitations, including inadequate viral suppression, drug resistance, and adverse reactions, several HBV entry inhibitors have shown promising clinical efficacy. To overcome the challenges posed by NUCs or monotherapy, the combination of immunotherapy and novel antiviral agents presents a promising avenue for future CHB treatment and potential cure.

Unconventional T cells, including mucosal-associated invariant T (MAIT), natural killer T (NKT), and gamma-delta T (γδT) cells, comprise distinct T-bet+, IFN-γ+ and RORγt+, IL-17+ subsets which play differential roles in health and disease. NKT1 cells are susceptible to ARTC2-mediated P2X7 receptor (P2RX7) activation, but the effects on other unconventional T-cell types are unknown. Here, we show that MAIT, γδT, and NKT cells express P2RX7 and are sensitive to P2RX7-mediated cell death. Mouse peripheral T-bet+ MAIT1, γδT1, and NKT1 cells, especially in liver, co-express ARTC2 and P2RX7. These markers could be further upregulated upon exposure to retinoic acid. Blocking ARTC2 or inhibiting P2RX7 protected MAIT1, γδT1, and NKT1 cells from cell death, enhanced their survival in vivo, and increased the number of IFN-γ-secreting cells without affecting IL-17 production. Importantly, this revealed the existence of IFN-γ and IL-4 co-producing unconventional T-cell populations normally lost upon isolation due to ARTC2/P2RX7-induced death. Administering extracellular NAD in vivo activated this pathway, depleting P2RX7-sensitive unconventional T cells. Our study reveals ARTC2/P2RX7 as a common regulatory axis modulating the unconventional T-cell compartment, affecting the viability of IFN-γ- and IL-4-producing T cells, offering important insights to facilitate future studies into how these cells can be regulated in health and disease.

Immune-mediated kidney diseases, including glomerulonephritis (GN), represent a diverse spectrum of disorders characterized by inflammation within the glomerulus and other renal compartments. Despite recent advances, the immunopathogenesis of these diseases remains incompletely understood. Current therapeutic approaches based on nonspecific immunosuppression often result in suboptimal outcomes and significant side effects, highlighting the need for tailored interventions. The complexity of the immune system extends beyond classical T-cell immunity, with the emergence of unconventional T cells - γδ T cells, NKT cells, and MAIT cells - that exhibit a semi-invariant nature and unique functions that bridge innate and adaptive immunity. γδ T cells exhibit unique homing and activation mechanisms and respond to different ligands, implying a multifaceted role in immune regulation. The understanding of γδ T-cell involvement in kidney disease lags behind conventional T-cell research. However, advances in immune cell analysis technologies offer promising avenues for elucidating their precise functions. This review synthesizes the current knowledge on γδ T cells in renal diseases, explores potential therapeutic strategies, and presents a roadmap for future research directions.

Many studies in the past 20 years have identified a contribution of inflammation and immune mechanisms to the pathophysiology of hypertension. Innate and adaptive immunity participate in this process. Among innate immune cells, macrophages and monocytes as well as dendritic cells, myeloid-derived suppressor cells, and neutrophils directly or via formation of neutrophil extracellular traps, play roles in the modulation of the inflammatory response in hypertension. Among adaptive immune cells, T and B cells have been implicated to varying degrees, particularly interleukin (IL)-17- and interferon γ-producing T lymphocytes, antagonized by T regulatory lymphocytes that are anti-inflammatory via production of IL-10. Among T cells that produce abundant IL-17, γδ T cells are unconventional T lymphocytes that are infrequent in the circulation in contrast to the much more abundant circulating αβ T lymphocytes, but are found mostly in tissues, and appear to play a role in triggering and sustaining inflammation in hypertension leading to vascular and renal injury. This review will provide an overview of these different immune cell phenotypes involved in the immune pathophysiology of hypertension and associated vascular disease.

Africa swine fever virus (ASFV) is the causative agent of African swine fever (ASF), a highly contagious hemorrhagic disease that can result in up to 100% lethality in both wild and domestic swine, regardless of breed or age. The ongoing ASF pandemic poses significant threats to the pork industry and food security, with serious implications for the sanitary and socioeconomic system. Due to the limited understanding of ASFV pathogenesis and immune protection mechanisms, there are currently no safe and effective vaccines or specific treatments available, complicating efforts for prevention and control. This review summarizes the current understanding of the intricate interplay between ASFV and the host immune system, encompassing both innate and adaptive immune responses to ASFV infection, as well as insights into ASFV pathogenesis and immunosuppression. We aim to provide comprehensive information to support fundamental research on ASFV, highlighting existing gaps and suggesting future research directions. This work may serve as a theoretical foundation for the rational design of protective vaccines against this devastating viral disease.

T- and natural killer (NK)-cell lymphomas are neoplasms derived from immature T cells (lymphoblastic lymphomas), or more commonly, from mature T and NK cells (peripheral T-cell lymphomas, PTCLs). PTCLs are rare but show marked biological and clinical diversity. They are usually aggressive and may present in lymph nodes, blood, bone marrow, or other organs. More than 30 T/NK-cell-derived neoplastic entities are recognized in the International Consensus Classification and the classification of the World Health Organization (fifth edition), both published in 2022, which integrate the most recent knowledge in hematology, immunology, pathology, and genetics. In both proposals, disease definition aims to integrate clinical features, etiology, implied cell of origin, morphology, phenotype, and genetic features into biologically and clinically relevant clinicopathologic entities. Cell derivation from innate immune cells or specific functional subsets of CD4+ T cells such as follicular helper T cells is a major determinant delineating entities. Accurate diagnosis of T/NK-cell lymphoma is essential for clinical management and mostly relies on tissue biopsies. Because the histological presentation may be heterogeneous and overlaps with that of many benign lymphoid proliferations and B-cell lymphomas, the diagnosis is often challenging. Disease location, morphology, and immunophenotyping remain the main features guiding the diagnosis, often complemented by genetic analysis including clonality and high-throughput sequencing mutational studies. This review provides a comprehensive overview of the classification and diagnosis of T-cell lymphoma in the context of current concepts and scientific knowledge.

Mucosal-associated invariant T (MAIT) cells are a subset of innate-like T cells abundant in human tissues that play a significant role in defense against bacterial and viral infections and in tissue repair. MAIT cells are activated by recognizing microbial-derived small-molecule ligands presented by the MHC class I related-1 protein. Although several MAIT cell modulators have been identified in the past decade, potent and chemically stable ligands remain limited. Herein, we carried out a structure-activity relationship study of ribityllumazine derivatives and found a chemically stable MAIT cell ligand with a pteridine core and a 2-oxopropyl group as the Lys-reactive group. The ligand showed high potency in a cocultivation assay using model cell lines of antigen-presenting cells and MAIT cells. The X-ray crystallographic analysis revealed the binding mode of the ligand to MR1 and the T cell receptor, indicating that it forms a covalent bond with MR1 via Schiff base formation. Furthermore, we found that the ligand stimulated proliferation of human MAIT cells in human peripheral blood mononuclear cells and showed an adjuvant effect in mice. Our developed ligand is one of the most potent among chemically stable MAIT cell ligands, contributing to accelerating therapeutic applications of MAIT cells.

The MHC class I-related 1 (MR1) molecule is a non-polymorphic antigen-presenting molecule that presents several metabolites to MR1-restricted T cells, including mucosal-associated invariant T (MAIT) cells. MR1 ligands bind to MR1 molecules by forming a Schiff base with the K43 residue of MR1, which induces the folding of MR1 and its reach to the cell surface. An antagonistic MR1 ligand, Ac-6-FP, and the K43A mutation of MR1 are known to inhibit the responses of MR1-restricted T cells. In this study, we analyzed MR1-restricted TCRs obtained from tumor-infiltrating lymphocytes (TILs) from breast cancer patients. They responded to two breast cancer cell lines independently from microbial infection and did not respond to other cancer cell lines or normal breast cells. Interestingly, the reactivity of these TCRs was not inhibited by Ac-6-FP, while it was attenuated by the K43A mutation of MR1. Our findings suggest the existence of a novel class of MR1-restricted TCRs whose antigen is expressed in some breast cancer cells and binds to MR1 depending on the K43 residue of MR1 but without being influenced by Ac-6-FP. This work provides new insight into the physiological roles of MR1 and MR1-restricted T cells.

Major histocompatibility complex class-1-related protein (MR1), unlike human leukocyte antigen (HLA) class-1, was until recently considered to be monomorphic. MR1 presents metabolites in the context of host responses to bacterial infection. MR1-restricted TCRs specific to tumor cells have been described, raising interest in their potential therapeutic application for cancer treatment. The diversity of MR1-ligand biology has broadened with the observation that single nucleotide variants (SNVs) exist within MR1 and that allelic variants can impact host immunity.

The TCR from a MR1-restricted T-cell clone, MC.7.G5, with reported cancer specificity and pan-cancer activity, was cloned and expressed in Jurkat E6.1 TCRαβ- β2M- CD8+ NF-κB:CFP NFAT:eGFP AP-1:mCherry cells or in human donor T cells. Functional activity of 7G5.TCR-T was demonstrated using cytotoxicity assays and by measuring cytokine release after co-culture with cancer cell lines with or without loading of previously described MR1 ligands. MR1 allele sequencing was undertaken after the amplification of the MR1 gene region by PCR. In vivo studies were undertaken at Labcorp Drug Development (Ann Arbor, MI, USA) or Epistem Ltd (Manchester, UK).

The TCR cloned from MC.7.G5 retained MR1-restricted functional cytotoxicity as 7G5.TCR-T. However, activity was not pan-cancer, as initially reported with the clone MC.7.G5. Recognition was restricted to cells expressing a SNV of MR1 (MR1*04) and was not cancer-specific. 7G5.TCR-T and 7G5-like TCR-T cells reacted to both cancer and healthy cells endogenously expressing MR1*04 SNVs, which encode R9H and H17R substitutions. This allelic specificity could be overcome by expressing supraphysiological levels of the wild-type MR1 (MR1*01) in cell lines.

Healthy individuals harbor T cells reactive to MR1 variants displaying self-ligands expressed in cancer and benign tissues. Described "cancer-specific" MR1-restricted TCRs need further validation, covering conserved allomorphs of MR1. Ligands require identification to ensure targeting MR1 is restricted to those specific to cancer and not normal tissues. For the wider field of immunology and transplant biology, the observation that MR1*04 may behave as an alloantigen warrants further study. .

Integrating single-cell datasets produced by multiple omics technologies is essential for defining cellular heterogeneity. Mosaic integration, in which different datasets share only some of the measured modalities, poses major challenges, particularly regarding modality alignment and batch effect removal. Here, we present a deep probabilistic framework for the mosaic integration and knowledge transfer (MIDAS) of single-cell multimodal data. MIDAS simultaneously achieves dimensionality reduction, imputation and batch correction of mosaic data by using self-supervised modality alignment and information-theoretic latent disentanglement. We demonstrate its superiority to 19 other methods and reliability by evaluating its performance in trimodal and mosaic integration tasks. We also constructed a single-cell trimodal atlas of human peripheral blood mononuclear cells and tailored transfer learning and reciprocal reference mapping schemes to enable flexible and accurate knowledge transfer from the atlas to new data. Applications in mosaic integration, pseudotime analysis and cross-tissue knowledge transfer on bone marrow mosaic datasets demonstrate the versatility and superiority of MIDAS. MIDAS is available at https://github.com/labomics/midas .

The "innate-like" T cell compartment, known as Tinn, represents a diverse group of T cells that straddle the boundary between innate and adaptive immunity. We explore the transcriptional landscape of Tinn compared to conventional T cells (Tconv) in the human thymus and blood using single-cell RNA sequencing (scRNA-seq) and flow cytometry. In human blood, the majority of Tinn cells share an effector program driven by specific transcription factors, distinct from those governing Tconv cells. Conversely, only a fraction of thymic Tinn cells displays an effector phenotype, while others share transcriptional features with developing Tconv cells, indicating potential divergent developmental pathways. Unlike the mouse, human Tinn cells do not differentiate into multiple effector subsets but develop a mixed type 1/type 17 effector potential. Cross-species analysis uncovers species-specific distinctions, including the absence of type 2 Tinn cells in humans, which implies distinct immune regulatory mechanisms across species.

Type I NKT cells, also known as Invariant Natural Killer T (iNKT) cells, are a subpopulation of unconventional, innate-like T (ILT) cells which can proficiently influence downstream immune effector functions. Type I NKT cells express a semi-invariant αβ T cell receptor (TCR) that recognises lipid-based ligands specifically presented by the non-classical cluster of differentiation (CD1) protein d (CD1d) molecule. Due to their potent immunomodulatory functional capacity, type I NKT cells are being increasingly considered in prophylactic and therapeutic approaches towards various diseases, including as vaccine-adjuvants. As viruses do not encode lipid synthesis, it is surprising that many studies have shown that some viruses can directly impede type I NKT activation through downregulating CD1d expression. Therefore, in order to harness type I NKT cells for potential anti-viral therapeutic uses, it is critical that we fully appreciate how the CD1d-iNKT cell axis interacts with viral immunity. In this review, we examine clinical findings that underpin the importance of type I NKT cell function in viral infections. This review also explores how certain viruses employ immunoevasive mechanisms and directly encode functions to target CD1d expression and type I NKT cell function. Overall, we suggest that the CD1d-iNKT cell axis may hold greater gravity within viral infections than what was previously appreciated.

T cell induced cellular immunity is considered to be extremely important for the control of tuberculosis (TB). T cell receptor (TCR), the key component responsible for the specificity and clustering of T cells, holds the potential to advance our understanding of T cell immunity against TB infection. This review systematically expounded the study progressions made in the field of TB-relevant TCRs based on single cell sequencing together with GLIPH2 technology and initiated a comparison of the T cell distribution between peripheral blood and infected organs. We divided clonal expanded T cell clones into recirculation subsets and local subsets to summarize their distinctions in clonal abundance, TCR sequences and antigenic specificity. Notably, local expansion appears to drive the primary variances in T cell subsets between these two contexts, indicating the necessity for further exploration into the functions and specificity of local subsets.

Primary sclerosing cholangitis (PSC) is a chronic inflammatory progressive cholestatic liver disease. Genetic risk factors, the presence of autoantibodies, the strong clinical link with inflammatory bowel disease, and associations with other autoimmune disorders all suggest a pivotal role for the immune system in PSC pathogenesis. In this review, we provide a comprehensive overview of recent immunobiology insights in PSC. A particular emphasis is given to immunological concepts such as tissue residency and knowledge gained from novel technologies, including single-cell RNA sequencing and spatial transcriptomics. This review of the immunobiological landscape of PSC covers major immune cell types known to be enriched in PSC-diseased livers as well as recently described cell types whose biliary localization and contribution to PSC immunopathogenesis remain incompletely described. Finally, we emphasize the importance of time and space in relation to PSC heterogeneity as a key consideration for future studies interrogating the role of the immune system in PSC.

Numerous developments have been achieved in the study and treatment of cancer throughout the decades that it has been common. After decades of research, about 100 different kinds of cancer have been found, each with unique subgroups within certain organs. This has significantly expanded our understanding of the illness. A mix of genetic, environmental, and behavioral variables contribute to the complicated and diverse process of cancer formation. Mutations, or changes in the DNA sequence, are crucial to the development of cancer. These mutations have the ability to downregulate the expression and function of Major Histocompatibility Complex class I (MHC I) and MHCII receptors, as well as activate oncogenes and inactivate tumor suppressor genes. Cancer cells use this tactic to avoid being recognized by cytotoxic CD8+T lymphocytes, which causes issues with antigen presentation and processing. This review goes into great length into the PI3K pathway, changes to MHC I, and positive impacts of tsMHC-II on disease-free survival and overall survival and the involvement of dendritic cells (DCs) in different tumor microenvironments. The vital functions that the PI3K pathway and its link to the mTOR pathway are highlighted and difficulties in developing effective cancer targeted therapies and feedback systems has also been mentioned, where resistance mechanisms include RAS-mediated oncogenic changes and active PI3K signalling.

The importance of unconventional T cells for mucosal immunity is firmly established but for systemic bacterial infection remains less well defined. In this study, we explored the role of various T cell subsets in murine Bartonella infection, which establishes persistent bacteremia unless controlled by antibacterial Abs. We found that αβ T cells are essential for Ab production against and clearance of B. taylorii, whereas MHC class I (MHC-I)- or MHC class II (MHC-II)-deficient mice eliminated B. taylorii infection with normal kinetics. Similarly, animals lacking either CD1d or MR1 suppressed bacteremia with normal kinetics. Interestingly, mice with a combined deficiency of either MHC-II and CD1d or MHC-II and MR1 failed to clear the infection, indicating that the combination of CD1d- and MR1-restricted T cells can compensate for the lack of MHC-II in this model. Our data document a previously underappreciated contribution of unconventional T cells to the control of systemic bacterial infection, supposedly as helper cells for antibacterial Ab production.

We intended to map the single-cell profile of OLP, explore the molecular characteristics of unconventional T cells in OLP tissues.

Buccal mucosa samples from OLP patients and healthy individuals were used to prepare single-cell suspension. Single-cell RNA sequencing was used to analyze the proportion of all the cells, and the molecular characteristics of unconventional T cells. Immunohistochemical staining was used to detect the expression of unconventional T cells marker genes.

The cell clusters from buccal mucosa were categorized into immune cells, fibroblasts, endothelial cells, and epithelial cells. Unconventional T cells with phenotype of CD247+TRDC+NCAM1+ were identified. Immunohistochemical staining revealed higher expression of unconventional T cell marker genes in OLP tissue, predominantly in the lamina propria. In OLP, unconventional T cells are in a unique stress response state, exhibited enhanced NF-κB signaling and apoptosis inhibition, enhanced heat shock protein genes expression, weakened cytotoxic function. A large number of ligand-receptor pairs were found between unconventional T cells and other cells, particularly with fibroblasts and endothelial cells.

This study mapped the single-cell profile of OLP, delineated the molecular characteristics of unconventional T cells in OLP, and uncovered that these unconventional T cells are in a stress response state.

Invariant natural killer T (iNKT) cells are a subset of lipid-reactive, unconventional T cells that have anti-tumor properties that make them a promising target for cancer immunotherapy. Recent studies have deciphered the developmental pathway of human MAIT and Vγ9Vδ2 γδ-T cells as well as murine iNKT cells, yet our understanding of human NKT cell development is limited. Here, we provide an update in our understanding of how NKT cells develop in the human body and how knowledge regarding their development could enhance human treatments by targeting these cells.