Novel insights into STIM1's role in store-operated calcium entry and its implications for T-cell mediated inflammation in trigeminal neuralgia.

This investigation aims to elucidate the novel role of Stromal Interaction Molecule 1 (STIM1) in modulating store-operated calcium entry (SOCE) and its subsequent impact on inflammatory cytokine release in T lymphocytes, thereby advancing our understanding of trigeminal neuralgia (TN) pathogenesis. Employing the Gene Expression Omnibus (GEO) database, we extracted microarray data pertinent to TN to identify differentially expressed genes (DEGs). A subsequent comparison with SOCE-related genes from the Genecards database helped pinpoint potential target genes. The STRING database facilitated protein-protein interaction (PPI) analysis to spotlight STIM1 as a gene of interest in TN. Through histological staining, transmission electron microscopy (TEM), and behavioral assessments, we probed STIM1's pathological effects on TN in rat models. Additionally, we examined STIM1's influence on the SOCE pathway in trigeminal ganglion cells using techniques like calcium content measurement, patch clamp electrophysiology, and STIM1- ORAI1 co-localization studies. Changes in the expression of inflammatory markers (TNF-α, IL-1ß, IL-6) in T cells were quantified using Western blot (WB) and enzyme-linked immunosorbent assay (ELISA) in vitro, while immunohistochemistry and flow cytometry were applied in vivo to assess these cytokines and T cell count alterations. Our bioinformatic approach highlighted STIM1's significant overexpression in TN patients, underscoring its pivotal role in TN's etiology and progression. Experimental findings from both in vitro and in vivo studies corroborated STIM1's regulatory influence on the SOCE pathway. Furthermore, STIM1 was shown to mediate SOCE-induced inflammatory cytokine release in T lymphocytes, a critical factor in TN development. Supportive evidence from histological, ultrastructural, and behavioral analyses reinforced the link between STIM1-mediated SOCE and T lymphocyte-driven inflammation in TN pathogenesis. This study presents novel evidence that STIM1 is a key regulator of SOCE and inflammatory cytokine release in T lymphocytes, contributing significantly to the pathogenesis of trigeminal neuralgia. Our findings not only deepen the understanding of TN's molecular underpinnings but also potentially open new avenues for targeted therapeutic strategies.

Light-Activated In Situ Vaccine with Enhanced Cytotoxic T Lymphocyte Infiltration and Function for Potent Cancer Immunotherapy.

In situ cancer vaccination is an attractive strategy that stimulates protective antitumor immunity. Cytotoxic T lymphocytes (CTLs) are major mediators of the adaptive immune defenses, with critical roles in antitumor immune response and establishing immune memory, and are consequently extremely important for in situ vaccines to generate systemic and lasting antitumor efficacy. However, the dense extracellular matrix and hypoxia in solid tumors severely impede the infiltration and function of CTLs, ultimately compromising the efficacy of in situ cancer vaccines. To address this issue, a robust in situ cancer vaccine, Au@MnO2 nanoparticles (AMOPs), based on a gold nanoparticle core coated with a manganese dioxide shell is developed. The AMOPs modulated the unfavorable tumor microenvironment (TME) to restore CTLs infiltration and function and efficiently induced immunogenic cell death. The Mn2+-mediated stimulator of the interferon genes pathway can be activated to further augment the therapeutic efficacy of the AMOPs. Thus, the AMOPs vaccine successfully elicited long-lasting antitumor immunity to considerably inhibit primary, recurrent, and metastatic tumors. This study not only highlights the importance of revitalizing CTLs efficacy against solid tumors but also makes progress toward overcoming TME barriers for sustained antitumor immunity.

Genetically engineering glycolysis in T cells increases their antitumor function.

BACKGROUND: T cells play a central role in the antitumor response. However, they often face numerous hurdles in the tumor microenvironment, including the scarcity of available essential metabolites such as glucose and amino acids. Moreover, cancer cells can monopolize these resources to thrive and proliferate by upregulating metabolite transporters and maintaining a high metabolic rate, thereby outcompeting T cells. METHODS: Herein, we sought to improve T-cell antitumor function in the tumor vicinity by enhancing their glycolytic capacity to better compete with tumor cells. To achieve this, we engineered human T cells to express a key glycolysis enzyme, phosphofructokinase, in conjunction with Glucose transporter 3, a glucose transporter. We co-expressed these, along with tumor-specific chimeric antigen or T-cell receptors. RESULTS: Engineered cells demonstrated an increased cytokine secretion and upregulation of T-cell activation markers compared with control cells. Moreover, they displayed superior glycolytic capacity, which translated into an improved in vivo therapeutic potential in a xenograft model of human tumors. CONCLUSION: In summary, these findings support the implementation of T-cell metabolic engineering to enhance the efficacy of cellular immunotherapies for cancer.

Influenza Virus-Derived CD8 T Cell Epitopes: Implications for the Development of Universal Influenza Vaccines.

The influenza virus poses a global health burden. Currently, an annual vaccine is used to reduce influenza virus-associated morbidity and mortality. Most influenza vaccines have been developed to elicit neutralizing Abs against influenza virus. These Abs primarily target immunodominant epitopes derived from hemagglutinin (HA) or neuraminidase (NA) of the influenza virus incorporated in vaccines. However, HA and NA are highly variable proteins that are prone to antigenic changes, which can reduce vaccine efficacy. Therefore, it is essential to develop universal vaccines that target immunodominant epitopes derived from conserved regions of the influenza virus, enabling cross-protection among different virus variants. The internal proteins of the influenza virus serve as ideal targets for universal vaccines. These internal proteins are presented by MHC class I molecules on Ag-presenting cells, such as dendritic cells, and recognized by CD8 T cells, which elicit CD8 T cell responses, reducing the likelihood of disease and influenza viral spread by inducing virus-infected cell apoptosis. In this review, we highlight the importance of CD8 T cell-mediated immunity against influenza viruses and that of viral epitopes for developing CD8 T cell-based influenza vaccines.

A phase 3, randomized, double-blind, multicenter, placebo-controlled study of S-588410, a five-peptide cancer vaccine as an adjuvant therapy after curative resection in patients with esophageal squamous cell carcinoma.

BACKGROUND: S-588410, a cancer peptide vaccine (CPV), comprises five HLA-A*24:02-restricted peptides from five cancer-testis antigens. In a phase 2 study, S-588410 was well-tolerated and exhibited antitumor efficacy in patients with urothelial cancer. Therefore, we aimed to evaluate the efficacy, immune response, and safety of S-588410 in patients with completely resected esophageal squamous cell carcinoma (ESCC). METHODS: This phase 3 study involved patients with HLA-A*24:02-positive and lymph node metastasis-positive ESCC who received neoadjuvant therapy followed by curative resection. After randomization, patients were administered S-588410 and placebo (both emulsified with Montanide™ ISA 51VG) subcutaneously. The primary endpoint was relapse-free survival (RFS). The secondary endpoints were overall survival (OS), cytotoxic T-lymphocyte (CTL) induction, and safety. Statistical significance was tested using the one-sided weighted log-rank test with the Fleming-Harrington class of weights. RESULTS: A total of 276 patients were randomized (N = 138/group). The median RFS was 84.3 and 84.1 weeks in the S-588410 and placebo groups, respectively (P = 0.8156), whereas the median OS was 236.3 weeks and not reached, respectively (P = 0.6533). CTL induction was observed in 132/134 (98.5%) patients who received S-588410 within 12 weeks. Injection site reactions (137/140 patients [97.9%]) were the most frequent treatment-emergent adverse events in the S-588410 group. Prolonged survival was observed in S-588410-treated patients with upper thoracic ESCC, grade 3 injection-site reactions, or high CTL intensity. CONCLUSIONS: S-588410 induced immune response and had acceptable safety but failed to reach the primary endpoint. A high CTL induction rate and intensity may be critical for prolonging survival during future CPV development.

Tolerance of radiotherapy with concomitant glofitamab in diffuse large B cell lymphoma: a case report.

Glofitamab, an anti-CD20 antibody, is approved as a third-line treatment for relapsed or refractory (r/r) diffuse large-cell B lymphoma (DLBCL), achieving a complete response in nearly 40% of patients. This humanized IgG1 bispecific monoclonal antibody binds to CD20 on malignant B lymphocytes and to CD3 on cytotoxic T cells. This dual binding forms an immunological synapse, activating T lymphocytes and leading to the lysis of tumor cells. Salvage radiotherapy is also effective for r/r DLBCL, but its combination with systemic treatments like glofitamab may increase radiation-induced toxicity. We report the first case of a patient with r/r DLBCL receiving concurrent salvage radiotherapy and glofitamab. A 68-year-old female diagnosed with stage IV DLBCL underwent initial treatment with R-CHOP, then Car-T cell therapy, followed by glofitamab for recurrence. Upon early metabolic progression detected by 18FDG-PET/CT, salvage radiotherapy was administered to the refractory site concurrently with glofitamab. The patient experienced mild para-spinal pain post-radiotherapy but no other significant toxicities. Three months post-treatment, she showed a complete metabolic response with no radiotherapy toxicity, as evidenced by PET-CT, and no signs of radiation pneumonitis. This case indicates that combining glofitamab with salvage radiotherapy is tolerable and suggests potential efficacy, warranting further investigation in prospective studies for r/r DLBCL.

Making a Monkey out of Human Immunodeficiency Virus/Simian Immunodeficiency Virus Pathogenesis: Immune Cell Depletion Experiments as a Tool to Understand the Immune Correlates of Protection and Pathogenicity in HIV Infection.

Understanding the underlying mechanisms of HIV pathogenesis is critical for designing successful HIV vaccines and cure strategies. However, achieving this goal is complicated by the virus's direct interactions with immune cells, the induction of persistent reservoirs in the immune system cells, and multiple strategies developed by the virus for immune evasion. Meanwhile, HIV and SIV infections induce a pandysfunction of the immune cell populations, making it difficult to untangle the various concurrent mechanisms of HIV pathogenesis. Over the years, one of the most successful approaches for dissecting the immune correlates of protection in HIV/SIV infection has been the in vivo depletion of various immune cell populations and assessment of the impact of these depletions on the outcome of infection in non-human primate models. Here, we present a detailed analysis of the strategies and results of manipulating SIV pathogenesis through in vivo depletions of key immune cells populations. Although each of these methods has its limitations, they have all contributed to our understanding of key pathogenic pathways in HIV/SIV infection.

Buyang huanwu decoction alleviates stroke-induced immunosuppression in MCAO mice by reducing splenic T cell apoptosis triggered by AIM2 inflammasome.

ETHNOPHARMACOLOGICAL RELEVANCE: Ischemic stroke is a serious disabling and fatal disease that places a heavy burden on the world. Stroke induces a state of systemic immunosuppression that is strongly associated with an increased risk of infection and severe outcomes. Buyang Huanwu Decoction (BYHWD) is an ancient Chinese traditional formula with a good clinical and experimental basis. However, the role of BYHWD on post-stroke immunomodulation, especially immunosuppression, is unclear. AIM OF THE STUDY: The aim of this study was to investigate the pharmacological mechanism of BYHWD to alleviate ischemic stroke by analyzing splenic T cells apoptosis triggered by the AIM2 inflammasome activation cascade. MATERIALS AND METHODS: An ischemic stroke model in C57BL/6 J mice was constructed using the MCAO method. The mNSS test and the hanging wire test were conducted to evaluate neurological impairment in mice. Histopathological damage was visualized by Nissl staining and HE staining. The protective effects of BYHWD on the spleen were determined by splenic index and spleen HE staining. The inhibition of AIM2 inflammasome cascade by BYHWD were explored through immunofluorescence (IF), flow cytometry, enzyme-linked immunosorbent assay (ELISA) and quantitative reverse transcription polymerase chain reaction (qRT-PCR). Flow cytometry was used to assess the apoptosis of splenic T cells. RESULTS: BYHWD significantly reduced infarct size, improved neurological function scores, and alleviated histopathological damage in middle cerebral artery occlusion (MCAO) mice. At the same time, BYHWD salvaged spleen atrophy. BYHWD significantly ameliorated apoptosis of splenic T lymphocytes. Key proteins and factors in the AIM2/IL-1ß/FasL/Fas axis are effectively inhibited from expression after BYHWD treatment. CONCLUSION: It is the first study to demonstrate that BYHWD can improve stroke-induced immunosuppression by down-regulating Fas-dependent splenic T-cell apoptosis triggered by peripheral AIM2 inflammasome-driven signaling cascade.

Increased CD56 expression after photodynamic therapy indicates an increased natural killer cell count following early photodynamic therapy for cutaneous squamous cell carcinoma.

Cutaneous squamous cell carcinoma (cSCC) is the second most common type of skin cancer. Photodynamic therapy (PDT) is a promising therapeutic method for managing cSCC due to its proven ability to target specific areas over time and its low risk of side effects. PDT may cause tissue damage and vascular shutdown, and may regulate local immunological responses. The present study aimed to investigate and compare the early lymphocyte modifications before and after PDT for SCC. A total of 10 patients with SCC were identified by pathological investigation. Initially, all wounds were treated with 20% aminolevulinic acid (ALA)-PDT as the initial stage in the therapeutic procedure. The wounds were treated by exposing them to red LED light with a wavelength of 635 nm, an energy density of 100 J/cm2 and an intensity of 80 mW/cm2. The tumor tissue was surgically removed 24 h later, and another round of PDT therapy was administered. Immunohistochemistry for CD3 and CD56 was conducted on the wound tissue post-surgery. If the wound showed granulation, necrosis or secretion, debridement was added to the therapy. All patients were monitored for 0.6-1.0 year post-treatment. ALA-PDT combination surgery fully controlled the tumor tissue in all 10 patients. The immunohistochemical analysis of the wound tissues showed that the expression of CD56 increased, while the expression of CD3 was not different after photodynamic therapy. These results also indirectly indicated that the overall count of NK cells in the 10 patients increased, nevertheless, there was no alteration in the T lymphocyte count. In conclusion, the ALA-PDT combination surgical therapy for cSCC demonstrates favorable results. An increase in CD56 expression may be a mechanism for the effective treatment of cSCC with PDT.

T-cell exhaustion in multiple myeloma.

INTRODUCTION: Chimeric Antigen Receptor (CAR) T-cells and Bispecific Antibodies (BsAb) are the leading platforms for redirecting the immune system against cells expressing the specific antigen, revolutionizing the treatment of hematological malignancies, including multiple myeloma (MM). In MM, drug-resistant relapses are the main therapy-limiting factor and the leading cause of why the disease is still considered incurable. T-cell-engaging therapies hold promise in improving the treatment of MM. However, the effectiveness of these treatments may be hindered by T-cell fitness. T-cell exhaustion is a condition of a gradual decline in effector function, reduced cytokine secretion, and increased expression of inhibitory receptors due to chronic antigen stimulation. AREAS COVERED: This review examines findings about T-cell exhaustion in MM in the context of T-cell redirecting BsAbs and CAR-T treatment. EXPERT OPINION: The fitness of T-cells has become an important factor in the development of T-cell redirecting therapies. The way T-cell exhaustion relates to these therapies could affect the further development of CAR and BsAbs technologies, as well as the strategies used for clinical use. Therefore, this review aims to explore the current understanding of T-cell exhaustion in MM and its relationship to these therapies.

Polyclonal but not monoclonal circulating memory CD4+ T cells attenuate the severity of Staphylococcus aureus bacteremia.

Staphylococcus aureus bacteremia causes significant morbidity and mortality. Treatment of staphylococcal infections is hindered by widespread antibiotic resistance, and attempts to develop an S. aureus vaccine have failed. Improved S. aureus treatment and infection prevention options require a deeper understanding of the correlates of protective immunity. CD4+ T cells have been identified as key orchestrators in the defense against S. aureus, but uncertainties persist regarding the subset, polarity, and breadth of the memory CD4+ T-cell pool required for protection. Here, using a mouse model of systemic S. aureus infection, we discovered that the breadth of bacterium-specific memory CD4+ T-cell pool is a critical factor for protective immunity against invasive S. aureus infections. Seeding mice with a monoclonal bacterium-specific circulating memory CD4+ T-cell population failed to protect against systemic S. aureus infection; however, the introduction of a polyclonal and polyfunctional memory CD4+ T-cell pool significantly reduced the bacterial burden. Our findings support the development of a multi-epitope T-cell-based S. aureus vaccine, as a strategy to mitigate the severity of S. aureus bacteremia.

Modifying T cell phenotypes using TYK2 inhibitor and its implications for the treatment of systemic lupus erythematosus.

OBJECTIVES: The tuning effects of JAK/TYK2 inhibitors on the imbalance between T follicular helper (Tfh) and T regulatory (Treg) cells, related to systemic lupus erythematosus (SLE) pathogenesis, were investigated using human peripheral blood samples. METHODS: Peripheral blood mononuclear cells from untreated patients with SLE and healthy controls were analysed. Tfh1 cells were identified in nephritis tissue, and the effect of Tfh1 cells on B-cell differentiation was examined by coculturing naïve B cells with Tfh1 cells. RESULTS: Tfh1 cell numbers were increased in the peripheral blood of patients, and activated Treg cell counts were decreased relative to Tfh1 cell counts. This imbalance in the Tfh to Treg ratio was remarkably pronounced in cases of lupus nephritis, especially in types III and IV active nephritis. Immunohistochemistry revealed Tfh1 cell infiltration in lupus nephritis tissues. Co-culture of Tfh1 cells (isolated from healthy individuals) with naïve B cells elicited greater induction of T-bet+ B cells than controls. In JAK/TYK2-dependent STAT phosphorylation assays using memory CD4+ T cells, IL-12-induced STAT1/4 phosphorylation and Tfh1 cell differentiation were inhibited by both JAK and TYK2 inhibitors. However, phosphorylation of STAT5 by IL-2 and induction of Treg cell differentiation by IL-2+TGFß were inhibited by JAK inhibitors but not by TYK2 inhibitors, suggesting that TYK2 does not mediate the IL-2 signalling pathway. CONCLUSIONS: Tfh1 cells can induce T-bet+ B cell production and may contribute to SLE pathogenesis-associated processes. TYK2 inhibitor may fine-tune the immune imbalance by suppressing Tfh1 differentiation and maintaining Treg cell differentiation, thereby preserving IL-2 signalling, unlike other JAK inhibitors.

CD8 T lymphocytes from B-1 cell-deficient mice down-regulates fungicidal activity of macrophages challenged with E. Cuniculi.

BACKGROUND: Encephalitozoon cuniculi is an opportunistic intracellular pathogen that establishes a balanced relationship with immunocompetent individuals depending on the activity of their CD8+ T cells lymphocytes. However, lower resistance to experimental infection with E. cuniculi was found in B-1 deficient mice (Xid), besides increased the number of CD8 T lymphocytes. Here, we evaluated the profile of CD8+ T lymphocytes from Balb/c wild-type (WT) or Balb/c Xid mice (with B-1 cell deficiency) on the microbicidal activity of macrophages challenged with E. cuniculi. METHODS: Naïve CD8 T lymphocytes from WT or Xid mice uninfected and primed CD8 T lymphocytes from WT or Xid mice infected with E cuniculi were co-cultured with macrophages previously challenged with E. cuniculi. We evaluated macrophages viability and microbicidal activity, and CD8 T lymphocytes viability and presence of activating molecules (CD62L, CD69, and CD107a). RESULTS: Macrophages co-cultured with naïve CD8 T lymphocytes from WT demonstrated high microbicidal activity. Naïve CD8 T lymphocytes obtained from WT mice had a higher expression of CD69 and LAMP-1-activating molecules compared to Xid CD8+ T lymphocytes. Primed CD8 T lymphocytes from Xid mice proliferated more than those from WT mice, however, when the expression of the activating molecule CD69 associated with the expression of CD62L was kept low. In conclusion, naïve CD8+ T lymphocytes from Xid mice, deficient in B-1 cells, they had reduced expression of activation molecules and cytotoxic activity.

Restoration of ARID1A Protein in ARID1A-deficient Clear Cell Carcinoma of the Ovary Attenuates Reactivity to Cytotoxic T Lymphocytes.

BACKGROUND/AIM: Clear cell carcinoma is a prevalent histological type of ovarian cancer in East Asia, particularly in Japan, known for its resistance to chemotherapeutic agents and poor prognosis. ARID1A gene mutations, commonly found in ovarian clear cell carcinoma (OCCC), contribute to its pathogenesis. Recent data revealed that the ARID1A mutation is related to better outcomes of cancer immunotherapy. Thus, this study aimed to investigate the immunotherapy treatment susceptibility of OCCC bearing ARID1A mutations. MATERIALS AND METHODS: Expression of ARID1A was analyzed using western blotting in ovarian cancer cell lines. OCCC cell lines JHOC-9 and RMG-V were engineered to overexpress NY-ESO-1, HLA-A*02:01, and ARID1A. Sensitivity to chemotherapy and T cell receptor-transduced T (TCR-T) cells specific for NY-ESO-1 was assessed in ARID1A-restored cells compared to ARID1A-deficient wild-type cells. RESULTS: JHOC-9 cells and RMG-V cells showed no expression of ARID1A protein. Overexpression of ARID1A in JHOC-9 and RMG-V cells did not impact sensitivity to gemcitabine. While ARID1A overexpression decreased sensitivity to cisplatin in RMG-V cells, it had no such effect in JHOC-9 cells. ARID1A overexpression reduced the reactivity of NY-ESO-1-specific TCR-T cells, as observed by the IFNγ ESLIPOT assay. CONCLUSION: Cancer immunotherapy is an effective approach to target ARID1A-deficient clear cell carcinoma of the ovary.

Peripheral Blood CD8+ T-Lymphocyte Immune Response in Benign and Subpopulations of Breast Cancer Patients.

Peripheral blood CD8+ T lymphocytes play a crucial role in cell-mediated immunity and tumor-related immune responses in breast cancer. In this study, label-free quantification analysis and gene set enrichment analysis (GSEA) of CD8+ T lymphocytes in the peripheral blood of benign patients and patients with different breast cancer (BC) subtypes, i.e., luminal A, luminal B, and triple-negative breast cancer (TNBC), were performed using nano-UHPLC and Orbitrap mass spectrometry. Differential protein expression in CD8+ T lymphocytes revealed significant downregulation (log2 FC ≥ 0.38 or ≤-0.38, adj. p < 0.05), particularly in proteins involved in cytotoxicity, cytolysis, and proteolysis, such as granzymes (GZMs) and perforin 1 (PRF1). This downregulation was observed in the benign group (GZMH, GZMM, and PRF1) and luminal B (GZMA, GZMH) subtypes, whereas granzyme K (GZMK) was upregulated in TNBC in comparison to healthy controls. The RNA degradation pathway was significantly downregulated (p < 0.05, normalized enrichment score (NES) from -1.47 to -1.80) across all BC subtypes, suggesting a potential mechanism for regulating gene expression during T cell activation. Also, the Sm-like proteins (LSM2, LSM3, and LSM5) were significantly downregulated in the RNA degradation pathway. Proteomic analysis of CD8+ T lymphocytes in peripheral blood across different breast cancer subtypes provides a comprehensive view of the molecular mechanisms of the systemic immune response that can significantly contribute to advancements in the diagnosis, treatment, and prognosis of this disease.

Imbalanced IL10/TGF-ß production by regulatory T-lymphocytes in patients with HTLV-1-associated myelopathy/ tropical spastic paraparesis.

BACKGROUND: Human T-cell lymphotropic virus type 1 (HTLV-1), also denominated Human T-cell leukemia virus-1, induces immune activation and secretion of proinflammatory cytokines, especially in individuals with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Regulatory T lymphocytes (Tregs) may control of inflammation through the production of regulatory cytokines, including IL10 and TGF-ß. In this study we determined the frequencies of CD4 + and CD8 + Tregs in a HAM/TSP population, compared to asymptomatic carriers and uninfected individuals, as well as investigated the profiles of regulatory and inflammatory cytokines. METHODS: Asymptomatic HTLV-1 carriers and HAM/TSP patients were matched by sex and age. The frequencies of IL10- and/or TGF-ß-producing Tregs were quantified by flow cytometry. Real-time reverse transcription polymerase chain reaction (RT-PCR) was used to quantify HTLV-1 proviral load and the mRNA expression of cytokines and cellular receptors in peripheral blood mononuclear cells. RESULTS: Total frequencies of CD4 + Tregs, as well as the IL10-producing CD4 + and CD8 + Treg subsets, were statistically higher in patients with HAM/TSP compared to asymptomatic HTLV-1-infected individuals. In addition, a positive correlation was found between the frequency of CD4 + IL10 + Tregs and proviral load in the HAM/TSP patients evaluated. A positive correlation was also observed between gene expression of proinflammatory versus regulatory cytokines only in HAM / TSP group. CONCLUSIONS: A higher frequencies of IL10-producing Tregs were identified in patients with HAM/TSP. Imbalanced production of IL10 in relation to TGF-ß may contribute to the increased inflammatory response characteristically seen in HAM/TSP patients.

Opposing tumor-cell-intrinsic and -extrinsic roles of the IRF1 transcription factor in antitumor immunity.

Type I interferon (IFN-I) and IFN-γ foster antitumor immunity by facilitating T cell responses. Paradoxically, IFNs may promote T cell exhaustion by activating immune checkpoints. The downstream regulators of these disparate responses are incompletely understood. Here, we describe how interferon regulatory factor 1 (IRF1) orchestrates these opposing effects of IFNs. IRF1 expression in tumor cells blocks Toll-like receptor- and IFN-I-dependent host antitumor immunity by preventing interferon-stimulated gene (ISG) and effector programs in immune cells. In contrast, expression of IRF1 in the host is required for antitumor immunity. Mechanistically, IRF1 binds distinctly or together with STAT1 at promoters of immunosuppressive but not immunostimulatory ISGs in tumor cells. Overexpression of programmed cell death ligand 1 (PD-L1) in Irf1-/- tumors only partially restores tumor growth, suggesting multifactorial effects of IRF1 on antitumor immunity. Thus, we identify that IRF1 expression in tumor cells opposes host IFN-I- and IRF1-dependent antitumor immunity to facilitate immune escape and tumor growth.

BACH2: The Future of Induced T-Regulatory Cell Therapies.

BACH2 (BTB Domain and CNC Homolog 2) is a transcription factor that serves as a central regulator of immune cell differentiation and function, particularly in T and B lymphocytes. A picture is emerging that BACH2 may function as a master regulator of cell fate that is exquisitely sensitive to cell activation status. In particular, BACH2 plays a key role in stabilizing the phenotype and suppressive function of transforming growth factor-beta (TGF-ß)-derived human forkhead box protein P3 (FOXP3)+ inducible regulatory T cells (iTregs), a cell type that holds great clinical potential as a cell therapeutic for diverse inflammatory conditions. As such, BACH2 potentially could be targeted to overcome the instability of the iTreg phenotype and suppressive function that has hampered their clinical application. In this review, we focus on the role of BACH2 in T cell fate and iTreg function and stability. We suggest approaches to modulate BACH2 function that may lead to more stable and efficacious Treg cell therapies.

Deciphering the Complex Immunopathogenesis of Alopecia Areata.

Alopecia areata (AA) is an autoimmune-mediated disorder in which the proximal hair follicle (HF) attack results in non-scarring partial to total scalp or body hair loss. Despite the growing knowledge about AA, its exact cause still needs to be understood. However, immunity and genetic factors are affirmed to be critical in AA development. While the genome-wide association studies proved the innate and acquired immunity involvement, AA mouse models implicated the IFN-γ- and cytotoxic CD8+ T-cell-mediated immune response as the main drivers of disease pathogenesis. The AA hair loss is caused by T-cell-mediated inflammation in the HF area, disturbing its function and disrupting the hair growth cycle without destroying the follicle. Thus, the loss of HF immune privilege, autoimmune HF destruction mediated by cytotoxic mechanisms, and the upregulation of inflammatory pathways play a crucial role. AA is associated with concurrent systemic and autoimmune disorders such as atopic dermatitis, vitiligo, psoriasis, and thyroiditis. Likewise, the patient's quality of life (QoL) is significantly impaired by morphologic disfigurement caused by the illness. The patients experience a negative impact on psychological well-being and self-esteem and may be more likely to suffer from psychiatric comorbidities. This manuscript aims to present the latest knowledge on the pathogenesis of AA, which involves genetic, epigenetic, immunological, and environmental factors, with a particular emphasis on immunopathogenesis.

Enhancement of systemic virus-specific T lymphocyte responses in pigs supplemented with algae-derived ß-glucan.

Algae-derived ß-glucan has been widely used as a feed additive in the swine industry. The supplementation of ß-glucan aims to improve growth performance and modulate the immunity of pigs. However, the potential effects of supplementing ß-glucan from algae on immune responses in pigs-specifically antigen-specific immunity-must be determined. In this study, the effects of algae-derived ß-glucan supplementation on growth performance, virus neutralising antibody and virus-specific T lymphocytes responses were investigated in pigs. Piglets (n=112 per treatment) were assigned to three treatments including non-supplemented group (control), ß-glucan 100 g/ton supplemented group (BG100), and ß-glucan 200 g/ton supplemented group (BG200). In this study, production performance of pigs was not found to be different between the experimental groups. Pigs supplemented with ß-glucan exhibited high levels of classical swine fever virus (CSFV)-specific producing T lymphocytes and neutralising antibody titer, compared to the control group. Interestingly, supplementation of ß-glucan significantly enhanced porcine reproductive and respiratory syndrome virus (PRRSV)-specific interferon-gamma (IFN-γ) producing T lymphocytes, including CD4+, CD8+, and CD4+CD8+ T lymphocyte subpopulations. Moreover, PRRS modified live vaccine (MLV) viremia was reduced in earlier for ß-glucan-supplemented pigs compared to the control group. The findings indicate that the algae-derived ß-glucan possesses biological potential as an immunomodulatory substance to enhance antiviral immunity, which may contribute to disease resistance in pigs.