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Current therapies for systemic lupus erythematosus that target a particular factor or cell type exhibit limited effectiveness. To address this limitation, our focus was on CD132, a subunit common to six inflammatory factor receptors implicated in SLE. Our study revealed heightened CD132 expression in SLE patients' lymphocytes, contributing to the production of pro-inflammatory cytokines and immunoglobulins. We developed a novel humanized anti-CD132 monoclonal antibody, named as 2D4. 2D4 efficiently blocked IL-21 and IL-15, with limited effectiveness against IL-2, thereby suppressing T and B cells without disrupting immune tolerance. In the mouse immunization model, 2D4 virtually inhibited T cell-dependent, antigen-specific B-cell response. In lupus murine models, 2D4 mitigated inflammation by suppressing multiple pro-inflammatory cytokines and anti-dsDNA antibody titers, also diminishing proteinuria and glomerulonephritis. Compared to Belimumab, 2D4 exhibited superior efficacy in ameliorating the inflammatory state and preserving renal function. Moreover, 2D4 exhibited the ability to inhibit the production of pro-inflammatory factors and autoantibodies in PBMCs from individuals with SLE, highlighting its therapeutic potential for SLE individuals. Potent, 2D4 has the potential to significantly improve clinical outcomes in SLE and other complex autoimmune disorders., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

X-irradiation of blood products is an alternative for gamma-ray to prevent post-transfusion GvHD. However, commercial X-irradiators are not widely available while little is known about their safety and efficacy for platelet products. This study introduces an efficient, accessible and cost-effective "X irradiation system" for platelet concentrates (PCs). By constructing a suitable radiation box (phantom) for a clinically available linear accelerator, an "X irradiation system" was designed specifically for PCs. PCs were divided into three equal bags either exposed to X- and gamma-irradiation or kept unirradiated (control). Irradiation-induced inhibition of T cells proliferation was examined by MTT and cell cycle assays on mononuclear cells (MNCs) obtained from PCs. The inhibitory effect of irradiation on allorecognition ability of MNCs was assessed by mixed lymphocyte reaction where MTT evaluated lymphocyte proliferation responses and flowcytometry examined CD8 + T lymphocytes activity. Platelet activation was also examined with P-selectin expression and PAC-1 binding by flowcytometry. X- and gamma-irradiation reduced T cell proliferation while disturbing the cell-cycle with reduced entry of T-cells into the S phase and their G2 arrest. Both types of irradiations also effectively reduced "lymphocyte allorecognition responses" while inactivating CD8 + T lymphocytes in platelet products but with no significant effect on platelet activity. This is the first study that showed "X irradiation system" effectively suppresses T cell proliferation and CD8 + T lymphocyte activity in platelet products, with no effect to platelet quality and activation markers. This may suggest the LINAC-based "X irradiation system" with a dose of 30Gy as efficient and safe as gamma-irradiation for platelet products., Competing Interests: Declarations Competing interests The authors declare no competing interests. Ethics approval This study was approved by the Ethics Committee of the High Institute for Research and Education in Transfusion Medicine, Tehran, Iran (Ethic approval numbers: IR.TMI.REC.1401.017& IR.TMI.REC.1402.001)., (© 2024. The Author(s).)

Specificity of a T cell receptor (TCR) is determined by the combination of its interactions to the peptide and human leukocyte antigen (HLA). TCR-based therapeutic molecules have to date targeted a single peptide in the context of a single HLA allele. Some peptides are presented on multiple HLA alleles, and by engineering TCRs for specific recognition of more than one allele, there is potential to expand the targetable patient population. Here, as a proof of concept, we studied two TCRs, S2 and S8, binding to the PRAME peptide antigen (ELFSYLIEK) presented by HLA alleles HLA-A*03:01 and HLA-A*11:01. By structure-guided affinity maturation targeting a specific residue on the HLA surface, we show that the affinity of the TCR can be modulated for different alleles. Using a combination of affinity maturation and functional T cell assay, we demonstrate that an engineered TCR can target the same peptide on two different HLA alleles with similar affinity and potency. This work highlights the importance of engineering alloselectivity for designing TCR based therapeutics suitable for differing global populations., (© 2024. The Author(s).)

Autoimmunity underlies many painful disorders, such as enthesopathies, which localize to the enthesis. From infiltration of the synovium and axial skeleton by B cells, to disturbances in the ratio of M1/M2 enthesis macrophages, to CD8 + T cell mediated inflammation, autoimmune dysregulation is becoming increasingly well characterized in enthesopathies. Tissue resident B cells, macrophages, neutrophils, and T cells have also been localized in healthy human entheses. However, the potential developmental origins, presence, and role of immune cells (ICs) in enthesis development is not known. Here, we use single-cell RNA-sequencing analysis to describe IC subtypes present in the enthesis before, during, and after mineralization, and to infer regulatory interactions between ICs and mesenchymal cells (MCs). We report the presence of nine phenotypically distinct IC subtypes, including B cells, macrophages, neutrophils, and T cells. We find that specific IC subtypes may promote MC-proliferation and differentiation, and that MCs may regulate IC phenotype and autoimmunity. Our findings suggest that bidirectional regulatory interactions between ICs and MCs may be important to enthesis mineralization, and suggest that progenitor MCs have a unique ability to limit autoimmunity during development., (© 2024. The Author(s).)

An effective vaccine against hepatitis C virus (HCV) should elicit both humoral and cellular immune responses. Previously, we characterized a bivalent vaccine candidate against hepatitis B (HBV) and HCV using chimeric HBV-HCV virus-like particles (VLP), in which the highly conserved epitope of HCV E2 glycoprotein (residues 412-425) was inserted into the hydrophilic loop of HBV small surface antigen (sHBsAg). While sHBsAg_412-425 elicited cross-neutralizing antibodies, it did not trigger a T-cell response against HCV. Thus, this study aimed to develop a vaccine candidate engaging both arms of adaptive immune response, potentially offering stronger protection against HCV. We evaluated the immunogenicity of minicircle (MC) DNA vaccines encoding sHBsAg_412-425 and HCV nonstructural (NS) proteins in BALB/c mice. Co-administration of sHBsAg_412-425 and NS induced a potent T-cell response, especially against NS3 and high titers of antibodies specific to HCV E2. Additionally, these antibodies recognized native HCV envelope glycoprotein heterodimers (E1E2) across multiple HCV genotypes and showed binding profiles to E1E2 alanine mutants comparable to the broadly neutralizing AP33 antibody. Overall, the findings demonstrate that MC DNA vaccine incorporating both sHBsAg_412-425 and HCV NS protein sequences induces robust, T-cell and AP33-like antibody responses, highlighting its potential as pan-genotypic prophylactic vaccine against HCV., (© 2024. The Author(s).)

ABL602 2 + 1, a bispecific antibody with two distinct domains binding to CLL-1 on leukemias and CD3 on T cells, exhibits superior T cell activation and tumour lysing activity. Treatment outcomes of bispecific antibody rely on acute myeloid leukemia cell replication and antibody induced tumour lysing, but their quantitative relationship was unknown. Mathematical models are employed to quantitatively investigate HL-60 cell kinetics determined by bispecific antibody and tumour burden. First, we analysed cytotoxicity assay data testing HL-60 cell against bispecific antibody and T cells, and found efficiency of bispecific antibody induced tumour lysing increases but saturates with increase of HL-60 cell, T cell and bispecific antibody concentration. As a result, their interaction leads to bistable HL-60 cell kinetics; namely, at a given bispecific antibody and T cell concentration interval, HL-60 cell kinetics with small tumour burdens are inhibited but refractory to large tumour burdens. T cell concentration is strong negatively correlated with HL-60 cell concentration. With bispecific antibody clearance, observed bistable HL-60 cell kinetics still exists. Our finding explains observed phenomenon that bispecific antibody was less efficacious at high tumour burden even with enough activated cytotoxic CD8 + T cells. Maintaining high antibody concentration and preventing T-cell exhaustion are equivalently important to sustain long-term control., (© 2024. The Author(s).)

Chronic hepatitis B (CHB) leads to liver inflammation and dysfunction, resulting in liver fibrosis and cancer. Nucleos(t)ide analogues (NAs), inhibitors of hepatitis B virus (HBV), specifically suppress HBV replication. We proposed that immune modulation benefits seroconversion by HBsAg loss. However, activation of T lymphocytes also deteriorates hepatic inflammation. Therefore, we intended to investigate the T cell status and its relationship with hepatic functions in CHB patients treated with NAs. Serum markers, including liver function markers AST, ALT, and HBV-infected markers HBV DNA, HBsAg, HBeAg, and HBsAb were measured in the clinical routine. The T cell levels and markers, including CD69, CD107a, CXCR3, and PD-1 were investigated using flow cytometry. Meanwhile, IFNγ, IL-2, and CXCL10 as immune activation markers in the PBMCs were investigated using qPCR. To validate the effects of NAs on T cell status, qPCR and flow cytometry were used to investigate the gene expression in the HepG2 and PLC5 cells treated with NAs, and in the healthy PBMCs treated with the cell-cultured supernatant. We found that NAs significantly suppressed HBV DNA and reduced AST and ALT levels in the CHB patients. Meanwhile, AST and ALT were both positively correlated with activation marker CD107a in CD8 + T cells. In addition, we found that the CHB patients with seroconversion exhibited a higher CD4/CD8 ratio (p < 0.05) compared to non-seroconversion. We demonstrated that NAs potentially induced IFNs and PD-L1 expression in HepG2 and PLC5 cells. Moreover, the collected supernatant from NAs-treated HepG2 significantly activated PBMCs. This study revealed that the reduction of HBV by NAs may be the reason leading to less AST and ALT levels. We further demonstrated that NAs induced IFN expression in hepatic cells to potentially activate T lymphocytes, which was positively associated with AST and ALT levels in the CHB patients. The results may explain the phenomena in clinical that when the virus is reactivated by aborted use of NAs, it causes consequent T cells-mediated severe acute-on-chronic liver injury., (© 2024. The Author(s).)

During of COVID-19 pandemic, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has continuously evolved, resulting in the emergence of several new variants of concerns (VOCs) with numerous mutations. These VOCs dominate in various regions due to increased transmissibility and antibody evasion, potentially reducing vaccine effectiveness. Nonetheless, it remains uncertain whether the recent SARS-CoV-2 VOCs have the ability to circumvent the T cell immunity elicited by either COVID-19 vaccination or natural infection. To address this, we conducted in-silico analysis to examine the impact of VOC-specific mutations at the epitope level and T cell cross-reactivity with the ancestral SARS-CoV-2. According to the in-silico investigation, T cell responses triggered by immunization or prior infections still recognize the variants in spite of mutations. These variants are expected to either maintain their dominant epitope HLA patterns or bind with new HLAs, unlike the epitopes of the ancestral strain. Our findings indicate that a significant proportion of immuno-dominant CD8 + and CD4 + epitopes are conserved across all the variants, implying that existing vaccines might maintain efficacy against new variations. However, further in-vitro and in-vivo studies are needed to validate the in-silico results and fully elucidate immune sensitivities to VOCs., (© 2024. The Author(s).)

Clinical evidence supports the notion that T cell exhaustion and terminal differentiation pose challenges to the persistence and effectiveness of chimeric antigen receptor-T (CAR-T) cells. MEK1/2 inhibitors (MEKIs), widely used in cancer treatment due to their ability to inhibit aberrant MAPK signaling, have shown potential synergistic effects when combined with immunotherapy. However, the impact and mechanisms of MEKIs on CAR-T cells remain uncertain and controversial. To address this, we conducted a comprehensive investigation to determine whether MEKIs enhance or impair the efficacy of CAR-T cells. Our findings revealed that MEKIs attenuated CAR-T cell exhaustion and terminal differentiation induced by tonic signaling and antigen stimulation, thereby improving CAR-T cell efficacy against hematological and solid tumors. Remarkably, these effects were independent of the specific scFvs and costimulatory domains utilized in CARs. Mechanistically, analysis of bulk and single-cell transcriptional profiles demonstrates that the effect of MEK inhibition was related to diminish anabolic metabolism and downregulation of c-Fos and JunB. Additionally, the overexpression of c-Fos or JunB in CAR-T cells counteracted the effects of MEK inhibition. Furthermore, our Cut-and-Tag assay revealed that MEK inhibition downregulated the JunB-driven gene profiles associated with exhaustion, differentiation, anergy, glycolysis, and apoptosis. In summary, our research unveil the critical role of the MAPK-c-Fos-JunB axis in driving CAR-T cell exhaustion and terminal differentiation. These mechanistic insights significantly broaden the potential application of MEKIs to enhance the effectiveness of CAR-T therapy., (© 2024. The Author(s).)

Primary mRNA vaccination against COVID-19 typically involves three doses for immunocompromised individuals, including hematopoietic stem cell transplantation (allo-HSCT) recipients. However, optimal subsequent boosting strategies remain unclear. This study aimed to assess the immunogenicity of a booster dose using the most recently updated vaccine (Comirnaty Omicron XBB.1.5) among long-term allo-HSCT survivors having previously received multiple mRNA vaccine doses, in median 4 (2-6). Thirty-four allo-HSCT recipients were enrolled at Sahlgrenska University Hospital, and peripheral blood samples were collected immediately before and four weeks after booster. Antibodies against the receptor-binding domain (anti-RBD) of spike 1 (S1) and nucleocapsid, as well as S1-specific ex vivo T-cell responses, were evaluated. Adverse events were monitored. Despite a median of 13 months since the prior vaccine dose, both humoral and T-cell responses against S1 were present in the pre-booster samples in all but two participants, who suffered from severe chronic Graft-versus-host disease. Notably, 62% of participants had a previously confirmed COVID-19 infection. Significantly higher pre-booster antibody levels were observed in women than men (p = 0.003). Booster dosing strengthened specific antibody and T cell responses and equalized pre-booster gender differences, although responses remained significantly lower among those receiving immunosuppressive treatment (p = 0.041). In a population of long-term allo-HSCT survivors, the majority of whom had a prior confirmed COVID-19 infection, both pre- and post-booster immune responses were robust. However, patients undergoing immunosuppressive treatment for GvHD exhibited significantly weaker responses., (© 2024. The Author(s).)

In recent years, clinical studies have shown positive results of the application of Mesenchymal Stromal Cells (MSCs) in severe cases of COVID-19. However, the mechanisms of immunomodulation of IFN-γ licensed MSCs in SARS-CoV-2 infection are only partially understood. In this study, we first tested the effect of IFN-γ licensing in the MSC immunomodulatory profile. Then, we established an in vitro model of inflammation by exposing Calu-3 lung cells to SARS-CoV-2 nucleocapsid and spike (NS) antigens, and determined the toxicity of SARS-CoV-2 NS antigen and/or IFN-γ stimulation to Calu-3. The conditioned medium (iCM) generated by Calu-3 cells exposed to IFN-γ and SARS-CoV-2 NS antigens was used to stimulate T-cells, which were then co-cultured with IFN-γ-licensed MSCs. The exposure to IFN-γ and SARS-CoV-2 NS antigens compromised the viability of Calu-3 cells and induced the expression of the inflammatory mediators ICAM-1, CXCL-10, and IFN-β by these cells. Importantly, despite initially stimulating T-cell activation, IFN-γ-licensed MSCs dramatically reduced IL-6 and IL-10 levels secreted by T-cells exposed to NS antigens and iCM. Moreover, IFN-γ-licensed MSCs were able to significantly inhibit T-cell apoptosis induced by SARS-CoV-2 NS antigens. Taken together, our data show that, in addition to reducing the level of critical cytokines in COVID-19, IFN-γ-licensed MSCs protect T-cells from SARS-CoV-2 antigen-induced apoptosis. Such observations suggest that MSCs may contribute to COVID-19 management by preventing the lymphopenia and immunodeficiency observed in critical cases of the disease., (© 2024. The Author(s).)

Tumor-associated macrophages (TAMs) have been implicated as a tumor microenvironment (TME) cell population, which may be playing a vital role in the inhibition of effective T cell responses in the prostate TME. In this manuscript, we leverage a novel microscale cell culture platform, known as Stacks, to investigate mono-, co-, and tri-culture TME models comprised of prostate tumor cell lines, primary macrophages, and autologous T cells from patients with prostate cancer. Through multiplexed analysis of these multi-cellular prostate tumor models, we capture a dynamic interaction between primary TAMs and activated T cells that resulted in reciprocal proinflammatory activation of both cell populations upon interaction. These findings suggest that activated T cells are capable of reprogramming immunosuppressive TAMs in the context of prostate tumor models and that TAM reprogramming may play a key supportive role in restoring proinflammatory T cell tumor responses in the prostate TME., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Liver transplantation is the definitive treatment for end-stage liver disease, yet T-cell mediated rejection (TCMR) remains a major challenge. This study aims to identify key genes associated with TCMR and their potential biological processes and mechanisms. The GSE145780 dataset was subjected to differential expression analysis, weighted gene co-expression network analysis (WGCNA), and machine learning algorithms to pinpoint key genes associated with TCMR. Gene Set Enrichment Analysis (GSEA), immune infiltration analysis, and regulatory networks were constructed to ascertain the biological relevance of these genes. Expression validation was performed using single-cell RNA-seq (scRNA-seq) data and liver biopsy tissues from patients. We identified 5 key genes (ITGB2, FCER1G, IL-18, GBP1, and CD53) that are associated with immunological functions, such as chemotactic activity, antigen processing, and T cell differentiation. GSEA highlighted enrichment in chemokine signaling and antigen presentation pathways. A lncRNA-miRNA-mRNA network was delineated, and drug target prediction yielded 26 potential drugs. Evaluation of expression levels in non-rejection (NR) and TCMR groups exhibited significant disparities in T cells and myeloid cells. Tissue analyses from patients corroborated the upregulation of GBP1, IL-18, CD53, and FCER1G in TCMR cases. Through comprehensive analysis, this research has identified 4 genes intimately connected with TCMR following liver transplantation, shedding light on the underlying immune activation pathways and suggesting putative targets for therapeutic intervention., (© 2024. The Author(s).)

Vaccination has been widely recognized as an effective measure for preventing infectious diseases. To facilitate quantitative research into the activation of adaptive immune responses in the human body by vaccines, it is important to develop an appropriate mathematical model, which can provide valuable guidance for vaccine development. In this study, we constructed a novel mathematical model to simulate the dynamics of antibody levels following vaccination, based on principles from immunology. Our model offers a concise and accurate representation of the kinetics of antibody response. We conducted a comparative analysis of antibody dynamics within the body after administering several common vaccines, including traditional inactivated vaccines, mRNA vaccines, and future attenuated vaccines based on defective interfering viral particles (DVG). Our findings suggest that booster shots play a crucial role in enhancing Immunoglobulin G (IgG) antibody levels, and we provide a detailed discussion on the advantages and disadvantages of different vaccine types. From a mathematical standpoint, our model proposes four essential approaches to guide vaccine design: enhancing antigenic T-cell immunogenicity, directing the production of high-affinity antibodies, reducing the rate of IgG decay, and lowering the peak level of vaccine antigen-antibody complexes. Our study contributes to the understanding of vaccine design and its application by explaining various phenomena and providing guidance in comprehending the interactions between antibodies and antigens during the immune process., (© 2024. The Author(s).)

Parkinson's disease (PD) is the most common progressive neurodegenerative movement disorder and results from the selective loss of dopaminergic neurons in the substantia nigra pars compacta. Pink1 and Parkin are proteins that function together in mitochondrial quality control, and when they carry loss-of-function mutations lead to familial forms of PD. While much research has focused on central nervous system alterations in PD, peripheral contributions to PD pathogenesis are increasingly appreciated. We report Pink1/Parkin regulate glycolytic and mitochondrial oxidative metabolism in peripheral blood mononuclear cells (PBMCs) from rats. Pink1/Parkin deficiency induces changes in the circulating lymphocyte populations, namely increased CD4 + T cells and decreased CD8 + T cells and B cells. Loss of Pink1/Parkin leads to elevated platelet counts in the blood and increased platelet-T cell aggregation. Platelet-lymphocyte aggregates are associated with increased thrombosis risk suggesting targeting the Pink1/Parkin pathway in the periphery might have therapeutic potential., (© 2024. The Author(s).)

Natural killer group 2 member D ligands (NKG2DLs) are expressed as stress response proteins in cancer cells. NKG2DLs induce immune cell activation or tumor escape responses, depending on their expression. Human pancreatic cancer cells, PANC-1, express membrane MHC class I polypeptide-related sequence A/B (mMICA/B), whereas soluble MICB (sMICB) is detected in the culture supernatant. We hypothesized that sMICB saturates NKG2D in NKG2D Low T cells and inhibits the activation signal from mMICB to NKG2D. Knockdown of MICB by siRNA reduced sMICB level, downregulated mMICB expression, maintained NKG2D Low T cell activation, and inhibited NKG2D High T cell activation. To maintain mMICB expression and downregulate sMICB expression, we inhibited a disintegrin and metalloproteinase (ADAM), a metalloproteinase that sheds MICB. Subsequently, the shedding of MICB was prevented using ADAM17 inhibitors, and the activation of NKG2D Low T cells was maintained. In vivo xenograft model revealed that NKG2D High T cells have superior anti-tumor activity. These results elucidate the mechanism of immune escape via sMICB and show potential for the activation of NKG2D Low T cells within the tumor microenvironment., (© 2024. The Author(s).)

Muscle stem cells (MuSCs) are effective in treating inflammatory diseases driven by overactive innate immune responses, such as colitis and acute lung injury, due to their immunomodulatory properties. However, their potential in treating diseases driven by adaptive immune responses is still uncertain. When primed with inflammatory cytokines, MuSCs strongly suppressed T cell activation and proliferation in vitro in co-culture with activated splenocytes or peripheral blood mononuclear cells. Systemic administration of MuSCs from both mice and humans alleviated pathologies in mice with concanavalin A-induced acute liver injury, characterized by hyperactivated T lymphocytes. Importantly, MuSCs showed significant species-specific differences in their immunoregulatory functions. In mouse MuSCs (mMuSCs), deletion or inhibition of inducible nitric oxide synthase (iNOS) reduced their immunosuppressive activity, and absence of iNOS negated their therapeutic effects in liver injury. Conversely, in human MuSCs (hMuSCs), knockdown or inhibition of indoleamine 2,3-dioxygenase (IDO) eliminated their immunosuppressive effects, and loss of IDO function rendered hMuSCs ineffective in treating liver injury in mice. These results reveal significant species-specific differences in the mechanisms by which MuSCs mediate T cell immunosuppression. Mouse MuSCs rely on iNOS, while human MuSCs depend on IDO expression. This highlights the need to consider species-specific responses when evaluating MuSCs' therapeutic potential in immune-related disorders., (© 2024. The Author(s).)

Background: Immunoglobulin derived AL amyloidosis and transthyretin derived ATTR amyloidosis are the most common forms of cardiac amyloidosis. Both may present with cardiac arrhythmias, heart failure, and extracardiac symptoms. Disease outcome is often fatal. Recently, it was proposed that amyloid may cause cardiac inflammation. Here we tested the hypothesis that immune cell infiltration in cardiac tissue correlates with clinicopathological patient characteristics., Patients and Methods: Myocardial biopsies from 157 patients with cardiac amyloidosis (46.5% AL, 53.3% ATTR) were immunohistochemically assessed for the presence and amount of T lymphocytes (CD3), macrophages (CD68) and neutrophils (MPO). Amyloid load, cardiomyocyte diameter, apoptosis (Caspase 3), necrosis (complement 9), and various clinical parameters were assessed and correlated with immune cell density., Results: Myocardial tissue was infiltrated with T lymphocytes (CD3), macrophages (CD68) and neutrophils (MPO) with variable amounts. Significant correlations were found between the number of macrophages and NYHA class. No correlations were found between the presence and amount of T lymphocytes, neutrophils and clinicopathological patient characteristics., Conclusion: The significant correlation between cardiac macrophage density and heart failure points towards a significant role of macrophages in disease pathology., (© 2024. The Author(s).)

To study the spatial interactions among cancer and non-cancer cells 1 , we here examined a cohort of 131 tumour sections from 78 cases across 6 cancer types by Visium spatial transcriptomics (ST). This was combined with 48 matched single-nucleus RNA sequencing samples and 22 matched co-detection by indexing (CODEX) samples. To describe tumour structures and habitats, we defined 'tumour microregions' as spatially distinct cancer cell clusters separated by stromal components. They varied in size and density among cancer types, with the largest microregions observed in metastatic samples. We further grouped microregions with shared genetic alterations into 'spatial subclones'. Thirty five tumour sections exhibited subclonal structures. Spatial subclones with distinct copy number variations and mutations displayed differential oncogenic activities. We identified increased metabolic activity at the centre and increased antigen presentation along the leading edges of microregions. We also observed variable T cell infiltrations within microregions and macrophages predominantly residing at tumour boundaries. We reconstructed 3D tumour structures by co-registering 48 serial ST sections from 16 samples, which provided insights into the spatial organization and heterogeneity of tumours. Additionally, using an unsupervised deep-learning algorithm and integrating ST and CODEX data, we identified both immune hot and cold neighbourhoods and enhanced immune exhaustion markers surrounding the 3D subclones. These findings contribute to the understanding of spatial tumour evolution through interactions with the local microenvironment in 2D and 3D space, providing valuable insights into tumour biology., (© 2024. The Author(s).)

Cancer immunotherapy aims to initiate or amplify immune responses that eliminate cancer cells and create immune memory to prevent relapse. Immune checkpoint inhibitors (ICIs), which target coinhibitory receptors on immune effector cells, such as CTLA-4 and PD-(L)1, have made significant strides in cancer treatment. However, they still face challenges in achieving widespread and durable responses. The effectiveness of anticancer immunity, which is determined by the interplay of coinhibitory and costimulatory signals in tumor-infiltrating immune cells, highlights the potential of costimulatory receptors as key targets for immunotherapy. This review explores our current understanding of the functions of CD2 and CD226, placing a special emphasis on their potential as novel agonist targets for cancer immunotherapy. CD2 and CD226, which are present mainly on T and NK cells, serve important functions in cell adhesion and recognition. These molecules are now recognized for their costimulatory benefits, particularly in the context of overcoming T-cell exhaustion and boosting antitumor responses. The importance of CD226, especially in anti-TIGIT therapy, along with the CD2‒CD58 axis in overcoming resistance to ICI or chimeric antigen receptor (CAR) T-cell therapies provides valuable insights into advancing beyond the current barriers of cancer immunotherapy, underscoring their promise as targets for novel agonist therapy., (© 2024. The Author(s).)

Despite a high response rate in chimeric antigen receptor (CAR) T cell therapy for acute lymphocytic leukaemia (ALL) 1-3 , approximately 50% of patients relapse within the first year 4-6 , representing an urgent question to address in the next stage of cellular immunotherapy. Here, to investigate the molecular determinants of ultralong CAR T cell persistence, we obtained a single-cell multi-omics atlas from 695,819 pre-infusion CAR T cells at the basal level or after CAR-specific stimulation from 82 paediatric patients with ALL enrolled in the first two CAR T ALL clinical trials and 6 healthy donors. We identified that elevated type 2 functionality in CAR T infusion products is significantly associated with patients maintaining a median B cell aplasia duration of 8.4 years. Analysis of ligand-receptor interactions revealed that type 2 cells regulate a dysfunctional subset to maintain whole-population homeostasis, and the addition of IL-4 during antigen-specific activation alleviates CAR T cell dysfunction while enhancing fitness at both transcriptomic and epigenomic levels. Serial proteomic profiling of sera after treatment revealed a higher level of circulating type 2 cytokines in 5-year or 8-year relapse-free responders. In a leukaemic mouse model, type 2 high CAR T cell products demonstrated superior expansion and antitumour activity, particularly after leukaemia rechallenge. Restoring antitumour efficacy in type 2 low CAR T cells was attainable by enhancing their type 2 functionality, either through incorporating IL-4 into the manufacturing process or by priming manufactured CAR T products with IL-4 before infusion. Our findings provide insights into the mediators of durable CAR T therapy response and suggest potential therapeutic strategies to sustain long-term remission by boosting type 2 functionality in CAR T cells., (© 2024. The Author(s).)

Despite recent advances in immunotherapies targeting single tumor-associated antigens, patients with multiple myeloma eventually relapse. ISB 2001 is a CD3 + T cell engager (TCE) co-targeting BCMA and CD38 designed to improve cytotoxicity against multiple myeloma. Targeting of two tumor-associated antigens by a single TCE resulted in superior cytotoxic potency across a variable range of BCMA and CD38 tumor expression profiles mimicking natural tumor heterogeneity, improved resistance to competing soluble factors and exhibited superior cytotoxic potency on patient-derived samples and in mouse models. Despite the broad expression of CD38 across human tissues, ISB 2001 demonstrated a reduced T cell activation profile in the absence of tumor cells when compared to TCEs targeting CD38 only. To determine an optimal first-in-human dose for the ongoing clinical trial ( NCT05862012 ), we developed an innovative quantitative systems pharmacology model leveraging preclinical data, using a minimum pharmacologically active dose approach, therefore reducing patient exposure to subefficacious doses of therapies., (© 2024. The Author(s).)

Traumatic injuries to the central nervous system (CNS) afflict millions of individuals worldwide 1 , yet an effective treatment remains elusive. Following such injuries, the site is populated by a multitude of peripheral immune cells, including T cells, but a comprehensive understanding of the roles and antigen specificity of these endogenous T cells at the injury site has been lacking. This gap has impeded the development of immune-mediated cellular therapies for CNS injuries. Here, using single-cell RNA sequencing, we demonstrated the clonal expansion of mouse and human spinal cord injury-associated T cells and identified that CD4 + T cell clones in mice exhibit antigen specificity towards self-peptides of myelin and neuronal proteins. Leveraging mRNA-based T cell receptor (TCR) reconstitution, a strategy aimed to minimize potential adverse effects from prolonged activation of self-reactive T cells, we generated engineered transiently autoimmune T cells. These cells demonstrated notable neuroprotective efficacy in CNS injury models, in part by modulating myeloid cells via IFNγ. Our findings elucidate mechanistic insight underlying the neuroprotective function of injury-responsive T cells and pave the way for the future development of T cell therapies for CNS injuries., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

T-cell activation is central for the initiation of T cell mediated adaptive immune response and is the result of the close communication between the Antigen Presenting Cell (APC) and the T lymphocyte. Although T-cell activation is currently well understood, and many intracellular pathways are well characterized, nevertheless new players are constantly identified, and this complements the known protein interactome. In this work we aimed to identify new proteins involved in T cell activation. We reviewed and analyzed results of microarray gene expression datasets reported in the public database GEO-NCBI. Using data from GSE136625, GSE50971, GSE13887, GSE11989 and GSE902 we performed different comparisons using R and other bioinformatic tools including GEO2R and we report here upregulated genes that have no previous reports in immune related functions and with potential participation upon T-cell activation. Our results indicate that RND3, SYT10, IgSF6 and PIN1 are potential new T-cell activation molecules., (© 2024. The Author(s).)

Psoriasis is a chronic, non-contagious, immune-mediated skin disorder. Inflammation of the skin's surface is characterised by scaly white, red, or silvery spots that occur due to the hyper-proliferation of keratinocytes in the epidermal layer. Primarily, pharmaceutical drugs or immune therapy are used to treat psoriasis. We are all aware that, certain therapeutic strategies can have some adverse effects, and over time, that hidden inflammation may manifest. This article introduces a mathematical model for psoriasis, formulated by employing a set of nonlinear ordinary differential equations (ODEs) that describe the densities of T-cells, dendritic cells (DCs), keratinocytes, and mesenchymal stromal cells (MSCs) as basic cell populations. A tumor necrosis factor- α ( T N F - α ) inhibitor has been imposed from the initial stage of the treatment regime, using the optimal control theoretic approach, and the numerical results have been observed. After 80 days of monitoring using only biologic T N F - α inhibitors, if this approach did not provide the intended outcomes (when severity arises), stem cells are administered a few times in a pulsed manner as a cell replacement technique in addition to this anti T N F - α medicine. We have observed the combined therapeutic benefit of stem cell replacement with a T N F - α inhibitor from a mathematical point of view. The theoretical analysis and the numerical results revealed that stem cell transplantation, along with a T N F - α inhibitor, is a promising psoriasis treatment option moving forward., (© 2024. The Author(s).)

Programming cell signaling during T-cell activation represents a simple strategy for improving the potency of therapeutic T-cell products. Stim-R technology (Lyell Immunopharma) is a customizable, degradable synthetic cell biomimetic that emulates physiologic, cell-like presentation of signal molecules to control T-cell activation. A breadth of Stim-R formulations with different anti-CD3/anti-CD28 (αCD3/αCD28) antibody densities and stoichiometries were screened for their effects on multiple metrics of T-cell function. We identified an optimized formulation that produced receptor tyrosine kinase-like orphan receptor 1 (ROR1)-targeted chimeric antigen receptor (CAR) T cells with enhanced persistence and polyfunctionality in vitro, as assessed in repeat-stimulation assays, compared with a benchmark product generated using a conventional T-cell-activating reagent. In transcriptomic analyses, CAR T cells activated with Stim-R technology showed downregulation of exhaustion-associated gene sets and retained a unique subset of stem-like cells with effector-associated gene signatures following repeated exposure to tumor cells. Compared with the benchmark product, CAR T cells activated using the optimized Stim-R technology formulation exhibited higher peak expansion, prolonged persistence, and improved tumor control in a solid tumor xenograft model. Enhancing T-cell products with Stim-R technology during T-cell activation may help improve therapeutic efficacy against solid tumors., (© 2024. The Author(s).)

Multiple investigations have demonstrated the crucial involvement of T-cell exhaustion (TEX) in anti-tumor immune response and their strong correlation with prognosis. This study aimed at creating a strong signature using TEX for gastric cancer through bioinformatics analysis and experimental validation. We utilized data from The Cancer Genome Atlas (TCGA) databases to retrieve RNA-seq data from patients with stomach adenocarcinoma (STAD). Genes related to TEX were discovered using gene set variance analysis (GSVA) and weighted gene correlation network analysis (WGCNA). Subsequently, prognostic signature based on TEX was developed using LASSO-Cox analysis. Relationship between key genes and immune cells were examined. Finally, biological function of a key TEX-related gene PTPRT in gastric cancer was verified by in vivo experiment. A total of 29 TEX-related biomarkers were screened by WGCNA and random forest. Among them, five core signatures (PTPRT, CAV2, PPIH, PRDM2, and FGF1), further identified by LASSO-Cox, were considered as strong predictors of prognosis for gastric cancer and associated with immune infiltration. PTPRT gene had the largest number of SNPs, with the most mutation types. In vivo experiments revealed that PTPRT overexpression significantly inhibited tumor malignant progression and accelerated apoptosis through stimulating the secretion of killer cytokines such as TNF-α and IFN-γ. In addition, flow cytometry revealed that PTPRT overexpression alleviated TEX by increasing the abundance of CD8+ T cells, with inhibition of cell surface PD-1 and Tim-3. The predictive prognostic value of TEX gene expression levels was evaluated in patients with gastric cancer, providing a new perspective for precision immuno-oncology studies., (© 2024. The Author(s).)

SARS-CoV-2 cell-mediated immunity remains understudied during pregnancy in unvaccinated Black African women living with HIV (WLWH) from low- and middle-income countries. We investigated SARS-CoV-2-specific T-cell responses 1 month following infection in 24 HIV-uninfected women and 15 WLWH at any stage during pregnancy or postpartum. The full-length spike (FLS) glycoprotein and nucleocapsid (N) protein of wild-type (WT) SARS-CoV-2, as well as mutated spike protein regions found in the Omicron variant (B.1.1.529) were targeted by flow cytometry. WT-specific CD4 + and CD8 + T cells elicited similar FLS- and N-specific responses in HIV-uninfected women and WLWH. SARS-CoV-2-specific T-lymphocytes were predominantly TNF-α monofunctional in pregnant and postpartum women living with and without HIV, with fever cells producing either IFN-γ or IL-2. Furthermore, T-cell responses were unaffected by Omicron-specific spike mutations as similar responses between Omicron and the ancestral virus were detected for CD4 + and CD8 + T cells. Our results collectively demonstrate comparable T-cell responses between WLWH on antiretroviral therapy and HIV-uninfected pregnant and postpartum women who were naïve to Covid-19 vaccination. Additionally, we show that T cells from women infected with the ancestral virus, Beta variant (B.1.351), or Delta variant (B.1.617.2) can cross-recognize Omicron, suggesting an overall preservation of T-cell immunity., (© 2024. The Author(s).)

In recent studies, we have established the unique adapter chimeric antigen receptor (CAR) platform RevCAR which uses, as an extracellular CAR domain, a peptide epitope instead of an antibody domain. RevCAR adapters (termed RevCAR target modules, RevTMs) are bispecific antibodies that enable the reversible ON/OFF switch of the RevCAR system, improving the safety compared to conventional CARs. Here, we describe for the first time its use for retargeting of both T and NK-92 cells. In addition, we describe the development and preclinical validation of a novel RevTM for targeting of the fibroblast growth factor-inducible 14 (Fn14) surface receptor which is overexpressed on Glioblastoma (GBM) cells, and therefore serves as a promising target for the treatment of GBM. The novel RevTM efficiently redirects RevCAR modified T and NK-92 cells and leads to the killing of GBM cells both in vitro and in vivo. Tumor cell killing is associated with increased IL-2, TNF-α and/or IFN-γ secretion. Hence, these findings give an insight into the complementary potential of both RevCAR T and NK-92 systems as a safe and specific immunotherapeutic approach against GBM., (© 2024. The Author(s).)

In the human and veterinary fields, oral vaccines generate considerable interest. In dogs, these vaccines are newly developed, and understanding their mechanisms is crucial. Mesenteric lymph nodes (MLNs) and Peyer's patches (PPs) are important sites for gastrointestinal mucosal induction, yet canine MLNs lack sufficient information. To address this, we collected MLN samples from healthy dogs, performed flow cytometry to characterize immune cells, and conducted single-cell RNA sequencing (scRNA-seq) to explore subpopulations, particularly B and T lymphocytes. This effort enabled the characterization of canine MLN's main cell populations and the construction of a predictive atlas, as well as the identification of particularities of this area., (© 2024. The Author(s).)

Systemic lupus erythematosus (SLE) is a multifactorial disease characterized by the convergence of genetic, immunological, and viral elements resulting in a complex interaction of both internal and external factors. The role of the Epstein-Barr virus (EBV) and human endogenous retroviruses (HERV-E) as triggers and maintenance elements in the pathogenesis of SLE has been widely recognized. Previous studies have independently evaluated the effects of EBV and HERV-E in this disease. In this work, for the first time, these viral factors are jointly investigated in SLE patients. This study aimed at assessing the differential expression of immune regulatory genes and the incidence of specific viral pathogens (EBV and HERV-E), alongside the detailed characterization of surface markers in T- and B-lymphocytes in patients with SLE and control participants. A comparative analysis between patients with SLE and control participants was performed, evaluating the expression of phenotypic markers and genes involved in the immune response (TNF-α, IL-2, IL-6, IL-10, IFNG, TLR3), as well as HERV-E gag and EBV viral genes (LMP1 and BZLF1).A significant association between SLE and EBV was found in this study. A notable increase in EBV LMP1 gene expression was observed in patients with SLE . Also, a significant overexpression of HERV-E was observed, in addition to a considerable increase in the distribution of the cell surface marker CD27 + on T- and B-lymphocytes, observed in individuals with SLE compared to the control group. This study provides evidence regarding the role that EBV virus plays in lymphocytes in the context of SLE, highlighting how both the virus and the host gene expression may influence disease pathogenesis by altering immune regulatory pathways mediated by TNF-α, IFN-γ, and IL-10, as well as parallel overexpression of HERV-E gag. The decrease in TLR3 could indicate a compromised antiviral response, which could facilitate viral reactivation and contribute to disease activity., (© 2024. The Author(s).)

Colorectal cancer (CRC) is a major contributor to global morbidity and mortality, necessitating more effective therapeutic approaches. T cells, prominent in the tumor microenvironment, exert a crucial role in modulating immunotherapeutic responses and clinical outcomes in CRC. This study introduces a pioneering method for characterizing the CRC immune microenvironment using single-cell sequencing data. Unlike previous approaches, which focused on individual T-cell signature genes, we utilized overall infiltration levels of colorectal cancer signature T-cells. Through weighted gene co-expression network analysis, Lasso regression, and StepCox analysis, we developed a prognostic risk model, TRGS (T-cell related genes signatures), based on six T cell-related genes. Multivariate Cox analysis identified TRGS as an independent prognostic factor for CRC, showcasing its superior predictive efficacy compared to existing immune-related prognostic models. Immunoreactivity analysis revealed higher Immunophenoscore and lower Tumor Immune Dysfunction and Exclusion scores in the low-risk group, indicating potential responsiveness to immune checkpoint inhibitor therapy. Additionally, patients in the low-risk group demonstrated heightened sensitivity to 5-fluorouracil-based chemotherapy regimens. In summary, TRGS emerges as a standalone prognostic biomarker for CRC, offering insights to optimize patient responses to immunotherapy and chemotherapy, thereby laying the groundwork for personalized tumor management strategies., (© 2024. The Author(s).)

Unpredictable fatal outcome of COVID-19 is attributed to dysregulated inflammation. Impaired early adaptive immune response leads to late-stage inflammatory outcome. The purpose of this study was to develop biomarkers for early detection of host immune impairment at first diagnosis from leftover RNA samples, which may in turn identify high risk patients. Leftover RNA samples of COVID-19 patients at first diagnosis were stored. Following prospective follow-up, the samples were shorted and categorized into outcome groups. Impaired adaptive T cell response (severity score) and Impaired IL-10 response (undetectable IL-10 in the presence of high expression of a representative interferon response gene) were determined by RT-PCR based assay. We demonstrate that a T cell response based 'severity score' comprising rational combination of Ct values of a target genes' signature can predict high risk noncomorbid potentially critical COVID-19 patients with a sensitivity of 91% (95% CI 58.7-99.8) and specificity of 92.6% (95% CI 75.7-99) (AUC:0.88). Although inclusion of comorbid patients reduced sensitivity to 77% (95% CI 54.6-92.2), the specificity was still 94% (95% CI 79.8-99.3) (AUC:0.82). The same for 'impaired IL-10 response' were little lower to predict high risk noncomorbid patients 64.2% (95% CI 35.1-87.2) and 82% (95% CI 65.5-93.2) respectively. Inclusion of comorbid patients drastically reduce sensitivity and specificity51.6% (95% CI 33.1-69.8) and 80.5% (95% CI 64.0-91.8) respectively. As best of our knowledge this is the first demonstration of a metric-based approach showing the 'severity score' as an indicator of early adoptive immune response, could be used as predictor of severe COVID-19 outcome at the time of first diagnosis using the same leftover swab RNA. The work flow could reduce expenditure and reporting time of the prognostic test for an earliest clinical decision ensuring possibility of early rational management., (© 2024. The Author(s).)

General anesthesia is thought to suppress the immune system and negatively affect postoperative infection and the long-term prognosis of cancer. However, the mechanism underlying immunosuppression induced by general anesthetics remains unclear. In this study, we focused on propofol, which is widely used for sedation under general anesthesia and intensive care and examined its effects on the T cell function and T cell-dependent immune responses. We found that propofol suppressed T cell glycolytic metabolism, differentiation into effector T cells, and cytokine production by effector T cells. CD8 T cells activated and differentiated into effector cells in the presence of propofol in vitro showed reduced antitumor activity. Furthermore, propofol treatment suppressed the increase in the number of antigen-specific CD8 T cells during Listeria infection. In contrast, the administration of propofol improved inflammatory conditions in mouse models of inflammatory diseases, such as OVA-induced allergic airway inflammation, hapten-induced contact dermatitis, and experimental allergic encephalomyelitis. These results suggest that propofol may reduce tumor and infectious immunity by suppressing the T cell function and T cell-dependent immune responses while improving the pathogenesis and prognosis of chronic inflammatory diseases by suppressing inflammation., (© 2024. The Author(s).)

Chimeric antigen receptor (CAR) T cells are effective against hematological cancers, but are less effective against solid tumors such as non-small cell lung cancer (NSCLC). One of the reasons is that only a few cell surface targets specific for NSCLC cells have been identified. Here, we report that CD98 heavy chain (hc) protein is overexpressed on the surface of NSCLC cells and is a potential target for CAR T cells against NSCLC. Screening of over 10,000 mAb clones raised against NSCLC cell lines showed that mAb H2A011 bound to NSCLC cells but not normal lung epithelial cells. H2A011 recognized CD98hc. Although CAR T cells derived from H2A011 could not be established presumably due to the high level of H2A011 reactivity in activated T cells, those derived from the anti-CD98hc mAb R8H283, which had been shown to lack reactivity with CD98hc glycoforms expressed on normal hematopoietic cells and some normal tissues, were successfully developed. R8H283 specifically reacted with NSCLC cells in six of 15 patients. R8H283-derived CAR T cells exerted significant anti-tumor effects in a xenograft NSCLC model in vivo. These results suggest that R8H283 CAR T cells may become a new therapeutic tool for NSCLC, although careful testing for off-tumor reactivity should be performed in the future., (© 2024. The Author(s).)

Cancer immunotherapy with chimeric antigen receptor (CAR) T cells can cause immune effector cell-associated neurotoxicity syndrome (ICANS). However, the molecular mechanisms leading to ICANS are not well understood. Here we examined the role of microglia using mouse models and cohorts of individuals with ICANS. CD19-directed CAR (CAR19) T cell transfer in B cell lymphoma-bearing mice caused microglia activation and neurocognitive deficits. The TGFβ-activated kinase-1 (TAK1)-NF-κB-p38 MAPK pathway was activated in microglia after CAR19 T cell transfer. Pharmacological TAK1 inhibition or genetic Tak1 deletion in microglia using Cx3cr1 CreER :Tak1 fl/fl mice resulted in reduced microglia activation and improved neurocognitive activity. TAK1 inhibition allowed for potent CAR19-induced antilymphoma effects. Individuals with ICANS exhibited microglia activation in vivo when studied by translocator protein positron emission tomography, and imaging mass cytometry revealed a shift from resting to activated microglia. In summary, we prove a role for microglia in ICANS pathophysiology, identify the TAK1-NF-κB-p38 MAPK axis as a pathogenic signaling pathway and provide a rationale to test TAK1 inhibition in a clinical trial for ICANS prevention after CAR19 T cell-based cancer immunotherapy., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

In vitro models of autoimmunity are constrained by an inability to culture affected epithelium alongside the complex tissue-resident immune microenvironment. Coeliac disease (CeD) is an autoimmune disease in which dietary gluten-derived peptides bind to the major histocompatibility complex (MHC) class II human leukocyte antigen molecules (HLA)-DQ2 or HLA-DQ8 to initiate immune-mediated duodenal mucosal injury 1-4 . Here, we generated air-liquid interface (ALI) duodenal organoids from intact fragments of endoscopic biopsies that preserve epithelium alongside native mesenchyme and tissue-resident immune cells as a unit without requiring reconstitution. The immune diversity of ALI organoids spanned T cells, B and plasma cells, natural killer (NK) cells and myeloid cells, with extensive T-cell and B-cell receptor repertoires. HLA-DQ2.5-restricted gluten peptides selectively instigated epithelial destruction in HLA-DQ2.5-expressing organoids derived from CeD patients, and this was antagonized by blocking MHC-II or NKG2C/D. Gluten epitopes stimulated a CeD organoid immune network response in lymphoid and myeloid subsets alongside anti-transglutaminase 2 (TG2) autoantibody production. Functional studies in CeD organoids revealed that interleukin-7 (IL-7) is a gluten-inducible pathogenic modulator that regulates CD8 + T-cell NKG2C/D expression and is necessary and sufficient for epithelial destruction. Furthermore, endogenous IL-7 was markedly upregulated in patient biopsies from active CeD compared with remission disease from gluten-free diets, predominantly in lamina propria mesenchyme. By preserving the epithelium alongside diverse immune populations, this human in vitro CeD model recapitulates gluten-dependent pathology, enables mechanistic investigation and establishes a proof of principle for the organoid modelling of autoimmunity., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

The mouse small intestine shows profound variability in gene expression along the crypt-villus axis 1,2 . Whether similar spatial heterogeneity exists in the adult human gut remains unclear. Here we use spatial transcriptomics, spatial proteomics and single-molecule fluorescence in situ hybridization to reconstruct a comprehensive spatial expression atlas of the adult human proximal small intestine. We describe zonated expression and cell type representation for epithelial, mesenchymal and immune cell types. We find that migrating enterocytes switch from lipid droplet assembly and iron uptake at the villus bottom to chylomicron biosynthesis and iron release at the tip. Villus tip cells are pro-immunogenic, recruiting γδ T cells and macrophages to the tip, in contrast to their immunosuppressive roles in mouse. We also show that the human small intestine contains abundant serrated and branched villi that are enriched at the tops of circular folds. Our study presents a detailed resource for understanding the biology of the adult human small intestine., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

While CAR-T and tgTCR-T therapies have exhibited noteworthy and promising outcomes in hematologic and solid tumors respectively, a set of distinct challenges remains. Consequently, the quest for novel strategies has become imperative to safeguard and more effectively release the full functions of engineered T cells. These factors are intricately linked to the success of adoptive cell therapy. Recently, CRISPR-based technologies have emerged as a major breakthrough for maintaining T cell functions. These technologies have allowed the discovery of T cells' negative regulators such as specific cell-surface receptors, cell-signaling proteins, and transcription factors that are involved in the development or maintenance of T cell dysfunction. By employing a CRISPR-genic invalidation approach to target these negative regulators, it has become possible to prevent the emergence of hypofunctional T cells. This review revisits the establishment of the dysfunctional profile of T cells before delving into a comprehensive summary of recent CRISPR-gene invalidations, with each invalidation contributing to the enhancement of engineered T cells' antitumor capacities. The narrative unfolds as we explore how these advancements were discovered and identified, marking a significant advancement in the pursuit of superior adoptive cell therapy., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

While the effector cells that mediate anti-tumor immunity have historically been attributed to αβ T cells and natural killer cells, γδ T cells are now being recognized as a complementary mechanism mediating tumor rejection. γδ T cells possess a host of functions ranging from antigen presentation to regulatory function and, importantly, have critical roles in eliciting anti-tumor responses where other immune effectors may be rendered ineffective. Recent discoveries have elucidated how these differing functions are mediated by γδ T cells with specific T cell receptors and spatial distribution. Their relative resistance to mechanisms of dysfunction like T cell exhaustion has spurred the development of therapeutic approaches exploiting γδ T cells, and an improved understanding of these cells should enable more effective immunotherapies., (© 2024. Springer Nature America, Inc.)

Multisystem inflammatory syndrome in children (MIS-C) is a severe, post-infectious sequela of SARS-CoV-2 infection 1,2 , yet the pathophysiological mechanism connecting the infection to the broad inflammatory syndrome remains unknown. Here we leveraged a large set of samples from patients with MIS-C to identify a distinct set of host proteins targeted by patient autoantibodies including a particular autoreactive epitope within SNX8, a protein involved in regulating an antiviral pathway associated with MIS-C pathogenesis. In parallel, we also probed antibody responses from patients with MIS-C to the complete SARS-CoV-2 proteome and found enriched reactivity against a distinct domain of the SARS-CoV-2 nucleocapsid protein. The immunogenic regions of the viral nucleocapsid and host SNX8 proteins bear remarkable sequence similarity. Consequently, we found that many children with anti-SNX8 autoantibodies also have cross-reactive T cells engaging both the SNX8 and the SARS-CoV-2 nucleocapsid protein epitopes. Together, these findings suggest that patients with MIS-C develop a characteristic immune response to the SARS-CoV-2 nucleocapsid protein that is associated with cross-reactivity to the self-protein SNX8, demonstrating a mechanistic link between the infection and the inflammatory syndrome, with implications for better understanding a range of post-infectious autoinflammatory diseases., (© 2024. The Author(s).)

Hypertension remains the leading cause of morbidity and mortality worldwide. Despite its prevalence, the development of novel antihypertensive therapies has only recently accelerated, with novel agents not yet commercialized, leaving a substantial proportion of individuals resistant to existing treatments. The intricate pathophysiology of hypertension is now understood to involve chronic low-grade inflammation, which places the immune system in the spotlight as a potential target for new therapeutics. This review explores the factors that initiate and sustain an immune response in hypertension, offering insights into potential targets for new treatments. Several factors contribute to immune activation in hypertension, including diet and damage-associated molecular pattern (DAMP) generation. Diets rich in fat or sodium can promote inflammation by inducing intestinal barrier dysfunction and triggering salt-sensitive receptors in T cells and dendritic cells. DAMPs, such as extracellular adenosine triphosphate and heat-shock protein 70, are released during episodes of increased blood pressure, contributing to immune cell activation and inflammation. Unconventional innate-like γδ T cells contribute to initiating and maintaining an immune response through their potential involvement in antigen presentation and regulating cytokine-mediated responses. Immunologic memory, sustained through the formation of effector memory T cells after exposure to hypertensive insults, likely contributes to maintaining an immune response in hypertension. When exposed to hypertensive insults, these memory cells are rapidly activated and contribute to elevated blood pressure and end-organ damage. Evidence from human hypertension, although limited, supports the relevance of distinct immune pathways in hypertension, and highlights the potential of targeted immune interventions in human hypertension. Diet and acute bouts of high blood pressure result in the release of dietary triggers, neoantigens, and damage-associated molecular patterns (DAMPs), which promote immune system activation. Elements such as lipopolysaccharides (LPS), sodium, heat-shock protein (HSP)70, extracellular adenosine triphosphate (eATP), and growth arrest-specific 6 (GAS6) promote activation of innate immune cells such as dendritic cells (DCs) and monocytes (Mo) through their respective receptors (toll-like receptor [TLR]4, amiloride-sensitive epithelial sodium channel [ENaC], TLR2/4, P2X7 receptor [P2RX7], and Axl) leading to costimulatory molecule expression and interleukin (IL)-1β and IL-23 production. The neoantigens HSP70 and isolevuglandins (IsoLGs) are presented to T cells by DCs and possibly γδ T cells, triggering T cell activation, IL-17 and interferon (IFN)-γ production, and the formation of T effector memory (T EM ) cells in the kidney, perivascular adipose tissue, bone marrow, and spleen. Exposure of T EM cells to their cognate antigen or previous activating stimuli causes these cells rapid expansion and activation. Cumulatively, this inflammatory state contributes to hypertension and end-organ damage. The figure was created using images from smart.servier.com and is licensed under a Creative Commons Attribution 4.0 license (CC BY 4.0)., (© 2024. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Nasal vaccination elicits a humoral immune response that provides protection from airborne pathogens 1 , yet the origins and specific immune niches of antigen-specific IgA-secreting cells in the upper airways are unclear 2 . Here we define nasal glandular acinar structures and the turbinates as immunological niches that recruit IgA-secreting plasma cells from the nasal-associated lymphoid tissues (NALTs) 3 . Using intact organ imaging, we demonstrate that nasal vaccination induces B cell expansion in the subepithelial dome of the NALT, followed by invasion into commensal-bacteria-driven chronic germinal centres in a T cell-dependent manner. Initiation of the germinal centre response in the NALT requires pre-expansion of antigen-specific T cells, which interact with cognate B cells in interfollicular regions. NALT ablation and blockade of PSGL-1, which mediates interactions with endothelial cell selectins, demonstrated that NALT-derived IgA-expressing B cells home to the turbinate region through the circulation, where they are positioned primarily around glandular acinar structures. CCL28 expression was increased in the turbinates in response to vaccination and promoted homing of IgA + B cells to this site. Thus, in response to nasal vaccination, the glandular acini and turbinates provide immunological niches that host NALT-derived IgA-secreting cells. These cellular events could be manipulated in vaccine design or in the treatment of upper airway allergic responses., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)