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Frontiers in Systems Biology 2024Crosstalk between dendritic cells (DCs) and T cells plays a crucial role in modulating immune responses in natural and pathological conditions. DC-T cell crosstalk is...
Crosstalk between dendritic cells (DCs) and T cells plays a crucial role in modulating immune responses in natural and pathological conditions. DC-T cell crosstalk is achieved through contact-dependent (i.e., immunological synapse) and contact-independent mechanisms (i.e., cytokines). Activated DCs upregulate co-stimulatory signals and secrete proinflammatory cytokines to orchestrate T cell activation and differentiation. Conversely, activated T helper cells "license" DCs towards maturation, while regulatory T cells (Tregs) silence DCs to elicit tolerogenic immunity. Strategies to efficiently modulate the DC-T cell crosstalk can be harnessed to promote immune activation for cancer immunotherapy or immune tolerance for the treatment of autoimmune diseases. Here, we review the natural crosstalk mechanisms between DC and T cells. We highlight bioengineering approaches to modulate DC-T cell crosstalk, including conventional vaccines, synthetic vaccines, and DC-mimics, and key seminal studies leveraging these approaches to steer immune response for the treatment of cancer and autoimmune diseases.
PubMed: 38911455
DOI: 10.3389/fsysb.2024.1372995 -
Transplantation Direct Jul 2024The mammalian target of rapamycin inhibitor (mTORi) therapy after kidney transplantation is solely monitored pharmacokinetically, not necessarily reflecting...
BACKGROUND
The mammalian target of rapamycin inhibitor (mTORi) therapy after kidney transplantation is solely monitored pharmacokinetically, not necessarily reflecting PI3K-Akt-mTOR pathway blockade efficacy leading to potential under-or overimmunosuppression.
METHODS
In this cross-sectional study, phosphoflow cytometry was used to determine the efficacy of mTOR inhibition in peripheral T- and B-lymphocyte subsets by assessing p70S6 kinase (p70S6K) phosphorylation in renal transplant recipients upon treatment with a combination of either mTORi and calcineurin inhibitors (n = 18), or mTORi with mycophenolic acid (n = 9). Nine dialysis patients with end-stage renal disease and 17 healthy age-matched volunteers served as controls.
RESULTS
mTORi treatment reduced p70S6K phosphorylation in CD4, CD8 T, and CD19 B cells compared with healthy controls (HCs). Subpopulation analysis of CD4 T cells and CD19 B cells revealed a significant reduction of p70S6K phosphorylation in CD4CD45RACD25 Th cells ( < 0.05), CD24CD38 transitional B cells ( < 0.001), CD24CD38 memory B cells ( < 0.001), and CD24CD38-naive B cells ( < 0.05) upon mTORi treatment, whereas CD4CD45RACD25CD127 regulatory T cells and CD24CD38 plasmablasts were not affected. Compared with mTORi + mycophenolic acid therapy, mTORi + calcineurin inhibitor treatment exhibited an even stronger inhibition of p70S6K phosphorylation in CD4CD45RACD25 Th cells and CD8 T cells. However, trough levels of mTORi did not correlate with p70S6K phosphorylation.
CONCLUSIONS
mTORi selectively inhibited p70S6K phosphorylation in select lymphocyte subtypes. Assessing p70S6K phosphorylation by phosphoflow cytometry may serve as an approach to understand cell subset specific effects of mTORi providing detailed pharmacodynamic information for individualizing immunosuppression.
PubMed: 38911271
DOI: 10.1097/TXD.0000000000001666 -
Cellular Immunology Jun 2024CD147 is a T cell activation-associated molecule which is closely involved in the formation of the immune synapse (IS). However, the precise role of CD147 in T cell...
CD147 is a T cell activation-associated molecule which is closely involved in the formation of the immune synapse (IS). However, the precise role of CD147 in T cell activation and IS formation remains unclear. In the present study, we demonstrated that CD147 translocated to the IS upon T cell activation and was primarily distributed in the peripheral super molecular cluster (p-SMAC). The knock down of CD147 expression in T cells, but not in B cells, impaired IS formation. CD147 participated in IS formation between T cells and different types of antigen-presenting cells (APCs), including macrophages and dendritic cells. Ligation of CD147 with its monoclonal antibody (mAb) HAb18 effectively inhibited T cell activation and IL-2 secretion. CD98, a critical molecule interacting with CD147, was distributed in IS in a CD147-dependent way. Phosphorylation levels of T cell receptor (TCR) related molecules, like ZAP-70, ERK, and cJun, were down-regulated by CD147 ligation, which is crucial for the interaction of CD147 and TCR signaling transduction. CD147 is indispensable for the formation of immune synapses and plays an important role in the regulation of its function.
PubMed: 38909549
DOI: 10.1016/j.cellimm.2024.104845 -
Biomedicine & Pharmacotherapy =... Jun 2024The induction of immunological tolerance is a promising strategy for managing autoimmune diseases, allergies, and transplant rejection. Tregitopes, a class of peptides,... (Review)
Review
The induction of immunological tolerance is a promising strategy for managing autoimmune diseases, allergies, and transplant rejection. Tregitopes, a class of peptides, have emerged as potential agents for this purpose. They activate regulatory T cells, which are pivotal in reducing inflammation and promoting tolerance, by binding to MHC II molecules and facilitating their processing and presentation to Treg cells, thereby encouraging their proliferation. Moreover, Tregitopes influence the phenotype of antigen-presenting cells by attenuating the expression of CD80, CD86, and MHC class II while enhancing ILT3, resulting in the inhibition of NF-kappa B signaling pathways. Various techniques, including in vitro and in silico methods, are applied to identify Tregitope candidates. Currently, Tregitopes play a vital role in balancing immune activation and tolerance in clinical applications such as Pompe disease, diabetes-related antigens, and the prevention of spontaneous abortions in autoimmune diseases. Similarly, Tregitopes can induce antigen-specific regulatory T cells. Their anti-inflammatory effects are significant in conditions such as autoimmune encephalomyelitis, inflammatory bowel disease, and Guillain-Barré syndrome. Additionally, Tregitopes have been leveraged to enhance vaccine design and efficacy. Recent advancements in understanding the potential benefits and drawbacks of IVIG and the discovery of the function and mechanism of Tregitopes have introduced Tregitopes as a popular option for immune system modulation. It is expected that they will bring about a significant revolution in the management and treatment of autoimmune and immunological diseases. This article is a comprehensive review of Tregitopes, concluding with the potential of these epitopes as a therapeutic avenue for immunological disorders.
PubMed: 38908205
DOI: 10.1016/j.biopha.2024.116983 -
BMC Medical Genomics Jun 2024Collagen (COL) genes, play a key role in tumor invasion and metastasis, are involved in tumor extracellular matrix (ECM)-receptor interactions and focal adhesion...
BACKGROUND
Collagen (COL) genes, play a key role in tumor invasion and metastasis, are involved in tumor extracellular matrix (ECM)-receptor interactions and focal adhesion pathways. However, studies focusing on the diagnostic value of the COL4 family in stomach adenocarcinoma (STAD) are currently lacking.
METHODS
The TCGA database was employed to retrieve the clinical features and RNA sequencing expression profiles of patients with STAD. We conducted an investigation to examine the expression disparities between STAD and adjacent normal tissues. Kaplan-Meier survival analysis was utilized to assess their prognostic significance, while Spearman correlation analysis was employed to determine their association with immune checkpoint genes and immunomodulatory molecules. Furthermore, GO and KEGG analyses were performed on the COL4s-related genes, revealing potential biological pathways through gene set enrichment analysis (GSEA). Subsequently, we explored the extent of immune infiltration of the COL4 family in STAD using the TIMER database. Lastly, the expression levels of the COL4 family in STAD were further validated through quantitative PCR (qPCR) and western blot techniques.
RESULTS
The expression levels of COL4A1/2 were significantly upregulated, while COL4A5/6 were conspicuously downregulated in STAD. The survival analysis revealed that the upregulated COL4s indicated poorer overall survival, first progression and post-progression survival outcomes. Additionally, our findings demonstrated a positive correlation between the expressions of COL4A1/2/3/4 and the infiltration of immune cells, including CD8 + T cells, dendritic cells, macrophages, neutrophils and CD4 + T cells. Further correlation analysis uncovered a favorable association between the expression of COL4A1/2/3/4 and various crucial immunomodulatory molecules, immunological checkpoint molecules, and chemokines. Quantitative PCR analysis confirmed that the expression patterns of COL4A1/3/4/6 genes aligned with the finding from the TCGA database. However, gastric cancer cells exhibited downregulation of COL4A2. Consistently, the protein level of COL4A1 was elevated, whereas the protein level of COL4A2 was reduced in the gastric cancer cell lines.
CONCLUSION
COL4s could potentially serve as biomarkers for diagnosing and predicting the prognosis of STAD.
Topics: Stomach Neoplasms; Humans; Adenocarcinoma; Prognosis; Collagen Type IV; Gene Expression Regulation, Neoplastic; Male; Female; Biomarkers, Tumor; Middle Aged; Kaplan-Meier Estimate
PubMed: 38907304
DOI: 10.1186/s12920-024-01934-3 -
Nature Communications Jun 2024Epstein-Barr virus (EBV) infects more than 95% of adults worldwide and is closely associated with various malignancies. Considering the complex life cycle of EBV,...
Epstein-Barr virus (EBV) infects more than 95% of adults worldwide and is closely associated with various malignancies. Considering the complex life cycle of EBV, developing vaccines targeting key entry glycoproteins to elicit robust and durable adaptive immune responses may provide better protection. EBV gHgL-, gB- and gp42-specific antibodies in healthy EBV carriers contributed to sera neutralizing abilities in vitro, indicating that they are potential antigen candidates. To enhance the immunogenicity of these antigens, we formulate three nanovaccines by co-delivering molecular adjuvants (CpG and MPLA) and antigens (gHgL, gB or gp42). These nanovaccines induce robust humoral and cellular responses through efficient activation of dendritic cells and germinal center response. Importantly, these nanovaccines generate high levels of neutralizing antibodies recognizing vulnerable sites of all three antigens. IgGs induced by a cocktail vaccine containing three nanovaccines confer superior protection from lethal EBV challenge in female humanized mice compared to IgG elicited by individual NP-gHgL, NP-gB and NP-gp42. Importantly, serum antibodies elicited by cocktail nanovaccine immunization confer durable protection against EBV-associated lymphoma. Overall, the cocktail nanovaccine shows robust immunogenicity and is a promising candidate for further clinical trials.
Topics: Animals; Epstein-Barr Virus Infections; Antibodies, Neutralizing; Herpesvirus 4, Human; Humans; Female; Mice; Antibodies, Viral; Glycoproteins; Nanoparticles; Adjuvants, Immunologic; Lymphoma; Nanovaccines
PubMed: 38906867
DOI: 10.1038/s41467-024-49546-w -
Medicine Jun 2024Along with global aging, osteoarthritis (OA) appears to have a high incidence and disability rate, which seriously affects the quality of life of patients, making age a...
Along with global aging, osteoarthritis (OA) appears to have a high incidence and disability rate, which seriously affects the quality of life of patients, making age a major risk factor. However, the pathology of OA is under-researched, and there is no obvious and effective treatment. Research has demonstrated the importance of aging, inflammation, and immunology in the onset and course of OA. This study aims to anticipate therapeutic drugs based on critical genes associated with OA and to elucidate the roles of genes and possible biomarkers associated with inflammation, immunology, and cellular senescence in OA. The OA gene expression matrix was first obtained from the Gene Expression Omnibus database. Screening for OA significant differentially expressed genes by bioinformatics identification. Specific biological processes and related signaling pathways of the differential genes were enriched. Then elucidate the status of immune cell involvement in OA based on immune infiltration analysis. Finally predict therapeutic agents based on pivotal genes. A total of 198 differentially expressed genes were identified in OA, and TP53, EGFR, TGFB1, LEP, CD4, MAPK8, SCARB1, ADIPOQ, JAK2, and SERPINE1 were further identified as important hub genes. The enrichment results showed that the development of arthritis was mainly related to immune cell differentiation, amino acid metabolism and cellular senescence process. The validation of immune infiltration results indicated that NK_cells, CD4_Tcells, Macrophages, Monocytic_lineage, Dendritic_cells, Basophils, CD8+_naive_T-cells may play an important role in the immune process of OA. Key Drug Prediction of Hub Genes found that Halicin, Ruxolitinib, Tofacitinib, Clenoliximab, Baricitinib may be a key drug or component in the treatment of OA.
Topics: Humans; Osteoarthritis; Computational Biology; Biomarkers; Gene Expression Profiling; Piperidines; Pyrimidines; Pyrroles
PubMed: 38905428
DOI: 10.1097/MD.0000000000038430 -
Science Advances Jun 2024Autophagy-targeting chimera (AUTAC) has emerged as a powerful modality that can selectively degrade tumor-related pathogenic proteins, but its low bioavailability and...
Autophagy-targeting chimera (AUTAC) has emerged as a powerful modality that can selectively degrade tumor-related pathogenic proteins, but its low bioavailability and nonspecific distribution significantly restrict their therapeutic efficacy. Inspired by the guanine structure of AUTAC molecules, we here report supramolecular artificial Nano-AUTACs (GM NPs) engineered by AUTAC molecule GN [an indoleamine 2,3-dioxygenase (IDO) degrader] and nucleoside analog methotrexate (MTX) through supramolecular interactions for tumor-specific protein degradation. Their nanostructures allow for precise localization and delivery into cancer cells, where the intracellular acidic environment can disrupt the supramolecular interactions to release MTX for eradicating tumor cells, modulating tumor-associated macrophages, activating dendritic cells, and inducing autophagy. Specifically, the induced autophagy facilitates the released GN for degrading immunosuppressive IDO to further enhance effector T cell activity and inhibit tumor growth and metastasis. This study offers a unique strategy for building a nanoplatform to advance the field of AUTAC in tumor immunotherapy.
Topics: Immunotherapy; Animals; Mice; Humans; Autophagy; Cell Line, Tumor; Proteolysis; Neoplasms; Nanoparticles; Methotrexate; Indoleamine-Pyrrole 2,3,-Dioxygenase; Dendritic Cells
PubMed: 38905336
DOI: 10.1126/sciadv.adn8079 -
International Journal of Biological... 2024Atopic dermatitis (AD) is a common inflammation skin disease that involves dysregulated interplay between immune cells and keratinocytes. Interleukin-38 (IL-38), a...
Atopic dermatitis (AD) is a common inflammation skin disease that involves dysregulated interplay between immune cells and keratinocytes. Interleukin-38 (IL-38), a poorly characterized IL-1 family cytokine, its role and mechanism in the pathogenesis of AD is elusive. Here, we show that IL-38 is mainly secreted by epidermal keratinocytes and highly expressed in the skin and downregulated in AD lesions. We generated IL-38 keratinocyte-specific knockout mice ( ) and induced AD models by 2,4-dinitrofluorobenzene (DNFB). Unexpectedly, after treatment with DNFB, mice were less susceptible to cutaneous inflammation of AD. Moreover, keratinocyte-specific deletion of IL-38 suppressed the migration of Langerhans cells (LCs) into lymph nodes which results in disturbed differentiation of CD4T cells and decreased the infiltration of immune cells into AD lesions. LCs are a type of dendritic cell that reside specifically in the epidermis and regulate immune responses. We developed LC-like cells from mouse bone marrow (BM) and treated with recombined IL-38. The results show that IL-38 depended on IL-36R, activated the phosphorylated expression of IRAK4 and NF-κB P65 and upregulated the expression of CCR7 to promoting the migration of LCs, nevertheless, the upregulation disappeared with the addition of IL-36 receptor antagonist (IL-36RA), IRAK4 or NF-κB P65 inhibitor. Furthermore, after treatment with IRAK4 inhibitors, the experimental AD phenotypes were alleviated and so IRAK4 is considered a promising target for the treatment of inflammatory diseases. Overall, our findings indicated a potential pathway that IL-38 depends on IL-36R, leading to LCs migration to promote AD by upregulating CCR7 via IRAK4/NF-κB and implied the prevention and treatment of AD, supporting potential clinical utilization of IRAK4 inhibitors in AD treatment.
Topics: Animals; Dermatitis, Atopic; Langerhans Cells; Mice; Cell Movement; Mice, Knockout; Interleukin-1; Keratinocytes; Dinitrofluorobenzene; NF-kappa B; Interleukins
PubMed: 38904012
DOI: 10.7150/ijbs.93843 -
Frontiers in Aging Neuroscience 2024Alzheimer's disease (AD) is the most widespread neurodegenerative disease in the world. Previous studies have shown that peripheral immune dysregulation plays a...
INTRODUCTION
Alzheimer's disease (AD) is the most widespread neurodegenerative disease in the world. Previous studies have shown that peripheral immune dysregulation plays a paramount role in AD, but whether there is a protective causal relationship between peripheral immunophenotypes and AD risk remains ambiguous.
METHODS
Two-sample Mendelian randomization (MR) was performed using large genome-wide association study (GWAS) genetic data to assess causal effects between peripheral immunophenotypes and AD risk. Utilizing the genetic associations of 731 immune cell traits as exposures. We adopted the inverse variance weighted method as the primary approach. The Weighted median and MR-Egger regression methods were employed as supplements. Various sensitivity analyses were performed to assess the robustness of the outcomes.
RESULTS
Based on the IVW method, we identified 14 immune cell traits that significantly reduced the risk of AD, of which six demonstrated statistical significance in both IVW and Weighted median methods. Among the seven immune traits, four were related to regulatory T (Treg) cells : (1) CD25++ CD45RA- CD4 not regulatory T cell % T cell (odds ratio (OR) [95% confidence interval (CI)] = 0.96 [0.95, 0.98], adjusted = 1.17E-02), (2) CD25++ CD45RA- CD4 not regulatory T cell % CD4+ T cell (OR [95% CI] = 0.97 [0.96, 0.99], adjusted = 3.77E-02), (3) Secreting CD4 regulatory T cell % CD4 regulatory T cell (OR [95% CI] = 0.98 [0.97, 0.99], adjusted = 7.10E-03), (4) Activated & secreting CD4 regulatory T cell % CD4 regulatory T cell(OR [95% CI] = 0.98 [0.97, 0.99], adjusted = 7.10E-03). In addition, HLA DR++ monocyte % monocyte (OR [95% CI] = 0.93 [0.89, 0.98], adjusted = 4.87E-02) was associated with monocytes, and HLA DR on myeloid Dendritic Cell (OR [95% CI] = 0.93 [0.89, 0.97], adjusted = 1.17E-02) was related to dendritic cells (DCs).
CONCLUSION
These findings enhance the comprehension of the protective role of peripheral immunity in AD and provide further support for Treg and monocyte as potential targets for immunotherapy in AD.
PubMed: 38903900
DOI: 10.3389/fnagi.2024.1403077