ABSTRACT
Background: Chronic rhinosinusitis (CRS) is an inflammatory condition classified into chronic rhinosinusitis with nasal polyps (CRSwNP) and chronic rhinosinusitis without nasal polyps (CRSsNP). Th cells manage inflammatory cells in CRS. Suppressor of Cytokine Signaling (SOCS) proteins regulate Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway in Th cells by polarizing toward Th1, Th2, and Th17 cells. This study evaluated the levels of SOCS1,3,5 in CRS patients to find associations with Th cells. Methods: In this cross-sectional study, 20 CRSwNP patients, 12 CRSsNP patients, and 12 controls participated. The infiltration of CD4+ T cells was determined using immunohistochemistry. The expression of specific transcription factors and SOCS proteins was assessed using real-time PCR. Cytokine levels were evaluated using ELISA. SOCS protein levels were investigated using western blot analysis. Results: The expression of SOCS3 increased in the CRSwNP group compared to CRSsNP and control groups (p <0.001). SOCS3 protein levels increased in the CRSwNP group compared to CRSsNP (p <0.05) and control (p <0.001) groups. Although there was a significant difference in SOCS5 expression between CRSsNP and control groups, SOCS5 protein levels were significantly different between CRSsNP and control (p <0.001) and CRSwNP (p <0.05) groups. Conclusions: Targeted therapies may be suggested for CRS by modulating SOCS3 and SOCS5 proteins that are responsible for polarization of Th cells toward Th2 or Th1 cells, respectively. JAK-STAT pathway targeting, which encompasses numerous cells, can be limited to SOCS proteins to more effectively orchestrate Th cell differentiation.
Subject(s)
Rhinitis , Sinusitis , Suppressor of Cytokine Signaling 3 Protein , Suppressor of Cytokine Signaling Proteins , Humans , Sinusitis/metabolism , Sinusitis/immunology , Suppressor of Cytokine Signaling Proteins/metabolism , Chronic Disease , Male , Suppressor of Cytokine Signaling 3 Protein/metabolism , Rhinitis/metabolism , Rhinitis/immunology , Female , Adult , Middle Aged , T-Lymphocytes, Helper-Inducer/metabolism , T-Lymphocytes, Helper-Inducer/immunology , Cross-Sectional Studies , Nasal Polyps/metabolism , Cytokines/metabolism , Suppressor of Cytokine Signaling 1 Protein/metabolism , Suppressor of Cytokine Signaling 1 Protein/genetics , Signal Transduction , RhinosinusitisABSTRACT
Transcribed enhancer maps can reveal nuclear interactions underpinning each cell type and connect specific cell types to diseases. Using a 5' single-cell RNA sequencing approach, we defined transcription start sites of enhancer RNAs and other classes of coding and noncoding RNAs in human CD4+ T cells, revealing cellular heterogeneity and differentiation trajectories. Integration of these datasets with single-cell chromatin profiles showed that active enhancers with bidirectional RNA transcription are highly cell type-specific and that disease heritability is strongly enriched in these enhancers. The resulting cell type-resolved multimodal atlas of bidirectionally transcribed enhancers, which we linked with promoters using fine-scale chromatin contact maps, enabled us to systematically interpret genetic variants associated with a range of immune-mediated diseases.
Subject(s)
CD4-Positive T-Lymphocytes , Enhancer Elements, Genetic , Genetic Predisposition to Disease , Transcription Initiation Site , Transcription, Genetic , Humans , CD4-Positive T-Lymphocytes/immunology , Cell Differentiation , Chromatin/metabolism , Chromatin/genetics , Promoter Regions, Genetic , T-Lymphocytes, Helper-Inducer/immunology , Single-Cell Gene Expression Analysis , Atlases as TopicABSTRACT
T peripheral helper (Tph) cells are a newly discovered subtype of CD4+ T cells that have emerged as the counterpart of T follicular helper (Tfh) cells in the peripheral tissues. These two cell types share some common characteristics, such as high levels of PD1 and CXCL13 expression, but differ in the expression of transcription factors and chemokine receptors. Tph cells have been studied in relation to B cells' effector functions, including cytokines production and antibody-mediated immune responses. However, their role in the inflammatory-mediated development of malignancies remains poorly understood. Tph cells were initially identified in the synovium of rheumatoid arthritis patients and have since been found to be expanded in several autoimmune diseases. They have been linked to a worse prognosis in autoimmune conditions, but intriguingly, their presence has been correlated with better outcomes in certain types of cancer. The functions of Tph cells are still being investigated, but recent data suggests their involvement in the assembly of tertiary lymphoid structures (TLS). Furthermore, their interaction with B cells, which have been mainly described as possessing a memory phenotype, promotes their development. In this review, we explore the role of Tph cells in peripheral immune responses during cancer and autoimmune disorders.
Subject(s)
Autoimmune Diseases , Neoplasms , T-Lymphocytes, Helper-Inducer , Humans , Autoimmune Diseases/immunology , Neoplasms/immunology , T-Lymphocytes, Helper-Inducer/immunology , B-Lymphocytes/immunology , AnimalsABSTRACT
PDAC is a typical "cold tumor" characterized by low immune cell infiltration and a suppressive immune microenvironment. We previously observed the existence of a rare group of follicular helper T cells (Tfh) that could enhance antitumor immune responses by recruiting other immune cells in PDAC. In this study, we ectopically expressed BCL6 in CD4+ T cells, and successfully induced Tfh-like transdifferentiation in vitro. This strategy provided abundant Tfh-like cells (iTfhs) that can recruit CD8+ T cells like endogenous Tfhs. Subsequently, Chimeric Antigen Receptors (CARs) against both MSL (Mesothelin) and EPHA2 (Ephrin receptor A2) were used to modify iTfh cells, and the CAR-iTfh cells significantly improved infiltration and antitumor cytotoxicity of co-cultured CD8+ T cells. After that, combinatory administration of CAR-iTfh & CAR-CD8 T cell therapy displayed a better effect in repressing the PDAC tumors in xenograft mouse models, compared to conventional CAR-CD4 & CAR-CD8 combinations, and the models received the CAR-iTfh & CAR-CD8 T cells displayed a significantly improved survival rate. Our study revealed the plasticity of Thelper differentiation, expanded the source of Tfh-like cells for cell therapy, and demonstrated a novel and potentially more efficient cellular composition for CAR-T therapy.
Subject(s)
Cell Transdifferentiation , Immunotherapy, Adoptive , Pancreatic Neoplasms , Proto-Oncogene Proteins c-bcl-6 , Receptors, Chimeric Antigen , Animals , Humans , Pancreatic Neoplasms/therapy , Pancreatic Neoplasms/immunology , Pancreatic Neoplasms/pathology , Mice , Immunotherapy, Adoptive/methods , Proto-Oncogene Proteins c-bcl-6/genetics , Proto-Oncogene Proteins c-bcl-6/metabolism , Receptors, Chimeric Antigen/immunology , Receptors, Chimeric Antigen/genetics , Receptors, Chimeric Antigen/metabolism , Cell Transdifferentiation/immunology , CD4-Positive T-Lymphocytes/immunology , Xenograft Model Antitumor Assays , CD8-Positive T-Lymphocytes/immunology , Cell Line, Tumor , Tumor Microenvironment/immunology , Receptor, EphA2/immunology , Receptor, EphA2/genetics , T-Lymphocytes, Helper-Inducer/immunology , FemaleABSTRACT
Oral Squamous Cell Carcinoma (OSCC) is the most common malignant tumor of the oral cavity. Despite recent advances in the field of oral cancer therapy, including the introduction of immunotherapeutic approaches, the 5-year survival rate remains steadily assessed around 50%. Thus, there is an urgent need for new therapeutic strategies. After the characterization of the immune phenotype of three human OSCC cell lines (CAL-27, SCC-25, and SCC-4) and one mouse OSCC cell line (MOC2) showing their similarities to resected patient tumors, we explored for the first time an experimental preclinical model of therapeutic vaccination with mouse OSCC MOC2 cell line stably expressing MHC class II antigens after CIITA gene transfection (MOC2-CIITA). Mice injected with MOC2-CIITA reject or strongly retard tumor growth; more importantly, vaccinated animals that fully reject MOC2-CIITA tumors display anti-tumor immunological memory protective against challenge with parental MOC2 tumor cells. Further experiments of adoptive cell transfer or in vivo cell depletion show that both CD4+ and CD8+ T lymphocytes prove fundamental in tumor rejection. This unprecedented approach for oral cancer opens the way for possible future translation of novel immunotherapeutic strategies to the human setting for the treatment of this tumor.
Subject(s)
Cancer Vaccines , Carcinoma, Squamous Cell , Mouth Neoplasms , Animals , Mouth Neoplasms/immunology , Mouth Neoplasms/therapy , Mice , Humans , Cell Line, Tumor , Cancer Vaccines/immunology , Carcinoma, Squamous Cell/immunology , Carcinoma, Squamous Cell/therapy , T-Lymphocytes, Helper-Inducer/immunology , Vaccination , Trans-Activators/genetics , Trans-Activators/immunology , Female , Immunologic Memory , CD4-Positive T-Lymphocytes/immunology , Nuclear ProteinsABSTRACT
Coronary heart disease (CHD) is related to aberrant aggregation of immune cells in the plaques. This study focused on identification of abnormal T cell subtypes and inflammatory factors in CHD patients. To this end, the subtypes of T cells in peripheral blood of CHD patients (n=141) and healthy controls (n=46) were analyzed by flow cytometry. Plasma concentrations of cytokines were analyzed by multiplex assay. It was shown that the number of T helper cells producing granulocyte-macrophage CSF (GM-CSF) was higher in CHD patients in comparison with healthy controls. In addition, the fractions of Th1 and Th17 cells as well as the levels of IL-4, IL-5, IL-6, and IL-10 in CHD patients also surpassed the control values (p<0.05). However, the level of GM-CSF was insignificantly lower in CHD patients. Thus, we revealed a relationship between the number of T cells producing GM-CSF and the severity of CHD. Our results can be used to develop new potential biomarkers for CHD detection.
Subject(s)
Biomarkers , Coronary Disease , Granulocyte-Macrophage Colony-Stimulating Factor , Interleukin-6 , Humans , Granulocyte-Macrophage Colony-Stimulating Factor/blood , Granulocyte-Macrophage Colony-Stimulating Factor/metabolism , Male , Female , Coronary Disease/immunology , Coronary Disease/blood , Middle Aged , Biomarkers/blood , Interleukin-6/blood , Case-Control Studies , Interleukin-10/blood , Th17 Cells/immunology , Th17 Cells/metabolism , Th1 Cells/immunology , Th1 Cells/metabolism , Interleukin-4/blood , Aged , T-Lymphocytes, Helper-Inducer/immunology , T-Lymphocytes, Helper-Inducer/metabolism , Adult , Flow Cytometry , Interleukin-5ABSTRACT
Previous studies have demonstrated the efficacy and feasibility of an anti-viral vaccine strategy that takes advantage of pre-existing CD4+ helper T (Th) cells induced by Mycobacterium bovis bacille Calmette-Guérin (BCG) vaccination. This strategy uses immunization with recombinant fusion proteins comprised of a cell surface expressed viral antigen, such as a viral envelope glycoprotein, engineered to contain well-defined BCG Th cell epitopes, thus rapidly recruiting Th cells induced by prior BCG vaccination to provide intrastructural help to virus-specific B cells. In the current study, we show that Th cells induced by BCG were localized predominantly outside of germinal centers and promoted antibody class switching to isotypes characterized by strong Fc receptor interactions and effector functions. Furthermore, BCG vaccination also upregulated FcγR expression to potentially maximize antibody-dependent effector activities. Using a mouse model of Ebola virus (EBOV) infection, this vaccine strategy provided sustained antibody levels with strong IgG2c bias and protection against lethal challenge. This general approach can be easily adapted to other viruses, and may be a rapid and effective method of immunization against emerging pandemics in populations that routinely receive BCG vaccination.
Subject(s)
Antibodies, Viral , BCG Vaccine , Ebola Vaccines , Ebolavirus , Hemorrhagic Fever, Ebola , Animals , Mice , BCG Vaccine/immunology , Ebolavirus/immunology , Hemorrhagic Fever, Ebola/prevention & control , Hemorrhagic Fever, Ebola/immunology , Ebola Vaccines/immunology , Ebola Vaccines/administration & dosage , Antibodies, Viral/immunology , Antibodies, Viral/blood , T-Lymphocytes, Helper-Inducer/immunology , Vaccination/methods , Mice, Inbred C57BL , Female , Humans , Disease Models, Animal , Receptors, IgG/immunology , Vaccine Development , Immunoglobulin Class Switching , ImmunizationABSTRACT
Systemic lupus erythematosus (SLE) is a common autoimmune disease, and its pathogenesis mainly involves the aberrant activation of B cells through follicular helper T (Tfh) cells to produce pathogenic antibodies, which requires more effective and safe treatment methods. Dihydroartemisinin (DHA) is the main active ingredient of artemisinin and has immunosuppressive effects. In this study, in vitro experiments confirmed that DHA inhibited Tfh cell induction and weakened its auxiliary function in B cell differentiation; furthermore, DHA directly inhibited B cell activation, differentiation, and antibody production. Furthermore, a mouse model of SLE was established, and we confirmed that DHA significantly reduced the symptoms of SLE and lupus nephritis, and decreased serum immunoglobulin (Ig)G, IgM, IgA, and anti-dsDNA levels. Moreover, DHA reduced the frequencies of total Tfh cells, activated Tfh cells, and B cell lymphoma 6, and interleukin (IL)-21 levels in Tfh cells from the spleen and lymph nodes, as well as the levels of B cells, germinal center B cells, and plasma cells in the spleen, lymph nodes, and kidneys. Additionally, DHA inhibited Tfh cells by blocking IL-2-inducible T cell kinase (ITK) signaling and its downstream nuclear factor (NF)-κB, nuclear factor of activated T cell, and activating protein-1 pathways, and directly inhibited B cells by blocking Bruton's tyrosine kinase (BTK) signaling and the downstream NF-κB and Myc pathways. Overall, our results demonstrated that DHA inhibited Tfh cells by blocking ITK signaling and also directly inhibited B cells by blocking BTK signaling. Therefore, reducing the production of pathogenic antibodies might effectively treat SLE.
Subject(s)
Artemisinins , B-Lymphocytes , Lupus Erythematosus, Systemic , Artemisinins/pharmacology , Animals , Lupus Erythematosus, Systemic/drug therapy , Lupus Erythematosus, Systemic/immunology , Lupus Erythematosus, Systemic/metabolism , Mice , B-Lymphocytes/drug effects , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , T-Lymphocytes, Helper-Inducer/drug effects , T-Lymphocytes, Helper-Inducer/immunology , T-Lymphocytes, Helper-Inducer/metabolism , Female , T Follicular Helper Cells/immunology , T Follicular Helper Cells/drug effects , T Follicular Helper Cells/metabolism , Disease Models, Animal , Cell Differentiation/drug effectsABSTRACT
PROBLEM: Adenomyosis (AM) is associated with immune response and inflammation. However, the role of T cell subsets in AM development has not been thoroughly understood. METHOD OF STUDY: Patients with focal or diffuse AM were recruited. Serum cytokines were quantified by enzyme-linked immunosorbent assay (ELISA). Different T cell subsets in the blood and ectopic endometrium were determined by flow cytometry. RESULTS: Serum interleukin-6 (IL-6) and macrophage-colony-stimulating factor (GM-CSF) were increased in patients with focal or diffuse AM before focused ultrasound ablation surgery (FUAS), but not after FUAS. Compared with the healthy control, the frequencies of CD8+ interferon-gamma (IFN-γ)-expressing cytotoxic T lymphocytes (CTLs), interleukin-17A (IL-17A)-expressing Tc17 cells, CD4+ T helper 1 (Th1) cells, and GM-CSF-expressing T helper (ThGM) cells were up-regulated in the blood of patients with AM, especially those with diffuse AM. However, these changes were eradicated after FUAS. Meanwhile, the frequencies of these T cell subsets were positively correlated with the CA-125 level. Furthermore, these T cell subsets were also increased in ectopic endometrium. CONCLUSIONS: Our study delineates for the first time the presence of CTLs, Tc17 cells, Th1, and ThGM cells in the blood and ectopic endometrium in AM. The results imply that T cell response might impact AM development.
Subject(s)
Adenomyosis , Endometrium , Granulocyte-Macrophage Colony-Stimulating Factor , Th1 Cells , Humans , Female , Endometrium/immunology , Endometrium/pathology , Adult , Adenomyosis/immunology , Adenomyosis/blood , Adenomyosis/pathology , Th1 Cells/immunology , Granulocyte-Macrophage Colony-Stimulating Factor/metabolism , Granulocyte-Macrophage Colony-Stimulating Factor/blood , T-Lymphocytes, Cytotoxic/immunology , Middle Aged , Interleukin-17/metabolism , Interleukin-17/blood , Interleukin-6/blood , Interleukin-6/metabolism , Th17 Cells/immunology , T-Lymphocytes, Helper-Inducer/immunologyABSTRACT
Systemic lupus erythematosus (SLE) is prototypical autoimmune disease driven by pathological T cell-B cell interactions1,2. Expansion of T follicular helper (TFH) and T peripheral helper (TPH) cells, two T cell populations that provide help to B cells, is a prominent feature of SLE3,4. Human TFH and TPH cells characteristically produce high levels of the B cell chemoattractant CXCL13 (refs. 5,6), yet regulation of T cell CXCL13 production and the relationship between CXCL13+ T cells and other T cell states remains unclear. Here, we identify an imbalance in CD4+ T cell phenotypes in patients with SLE, with expansion of PD-1+/ICOS+ CXCL13+ T cells and reduction of CD96hi IL-22+ T cells. Using CRISPR screens, we identify the aryl hydrocarbon receptor (AHR) as a potent negative regulator of CXCL13 production by human CD4+ T cells. Transcriptomic, epigenetic and functional studies demonstrate that AHR coordinates with AP-1 family member JUN to prevent CXCL13+ TPH/TFH cell differentiation and promote an IL-22+ phenotype. Type I interferon, a pathogenic driver of SLE7, opposes AHR and JUN to promote T cell production of CXCL13. These results place CXCL13+ TPH/TFH cells on a polarization axis opposite from T helper 22 (TH22) cells and reveal AHR, JUN and interferon as key regulators of these divergent T cell states.
Subject(s)
Basic Helix-Loop-Helix Transcription Factors , CD4-Positive T-Lymphocytes , Chemokine CXCL13 , Interferon Type I , Lupus Erythematosus, Systemic , Proto-Oncogene Proteins c-jun , Receptors, Aryl Hydrocarbon , Female , Humans , Male , Basic Helix-Loop-Helix Transcription Factors/metabolism , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , Cell Differentiation , Chemokine CXCL13/metabolism , Epigenomics , Gene Expression Profiling , Interferon Type I/immunology , Interferon Type I/metabolism , Interleukin-22/immunology , Interleukin-22/metabolism , Lupus Erythematosus, Systemic/immunology , Lupus Erythematosus, Systemic/metabolism , Lupus Erythematosus, Systemic/genetics , Proto-Oncogene Proteins c-jun/metabolism , Receptors, Aryl Hydrocarbon/metabolism , T-Lymphocytes, Helper-Inducer/immunology , T-Lymphocytes, Helper-Inducer/metabolismABSTRACT
CD4+ T cells are central mediators of protective immunity to blood-stage malaria, particularly for their capacity in orchestrating germinal center reaction and generating parasite-specific high-affinity antibodies. T follicular helper (Tfh) cells are predominant CD4+ effector T cell subset implicated in these processes, yet the factors and detailed mechanisms that assist Tfh cell development and function during Plasmodium infection are largely undefined. Here we provide evidence that receptor for activated C kinase 1 (RACK1), an adaptor protein of various intracellular signals, is not only important for CD4+ T cell expansion as previously implied but also plays a prominent role in Tfh cell differentiation and function during blood-stage Plasmodium yoelii 17XNL infection. Consequently, RACK1 in CD4+ T cells contributes significantly to germinal center formation, parasite-specific IgG production, and host resistance to the infection. Mechanistic exploration detects specific interaction of RACK1 with STAT3 in P. yoelii 17XNL-responsive CD4+ T cells, ablation of RACK1 leads to defective STAT3 phosphorylation, accompanied by substantially lower amount of STAT3 protein in CD4+ T cells, whereas retroviral overexpression of RACK1 or STAT3 in RACK1-deficient CD4+ T cells greatly restores STAT3 activity and Bcl-6 expression under the Tfh polarization condition. Further analyses suggest RACK1 positively regulates STAT3 stability by inhibiting the ubiquitin-proteasomal degradation process, thus promoting optimal STAT3 activity and Bcl-6 induction during Tfh cell differentiation. These findings uncover a novel mechanism by which RACK1 participates in posttranslational regulation of STAT3, Tfh cell differentiation, and subsequent development of anti-Plasmodium humoral immunity.
Subject(s)
Cell Differentiation , Malaria , Plasmodium yoelii , Receptors for Activated C Kinase , STAT3 Transcription Factor , T Follicular Helper Cells , Animals , Receptors for Activated C Kinase/metabolism , STAT3 Transcription Factor/metabolism , Malaria/immunology , Malaria/parasitology , Mice , Plasmodium yoelii/immunology , T Follicular Helper Cells/immunology , T Follicular Helper Cells/metabolism , Mice, Inbred C57BL , T-Lymphocytes, Helper-Inducer/immunology , T-Lymphocytes, Helper-Inducer/metabolism , Mice, Knockout , Germinal Center/immunologyABSTRACT
Introduction: Circulating T follicular helper (cTfh) cells and circulating T peripheral helper (cTph) cells (which share common characteristics with the cTfh population) are implicated in the pathogenesis of immune-mediated and autoimmune diseases such as psoriasis (Ps). Their close interplay with the interleukin 17 (IL-17) axis and the ex vivo effect of IL-17-targeting biologic agents used to treat Ps on them are elusive. This study aimed to investigate the effect of biologics targeting IL-17 on cTfh and cTph cell subpopulations isolated from the blood of patients with Ps. Methods: Peripheral blood mononuclear cells (PBMCs) were isolated from patients with Ps at treatment initiation and three months later. Samples were also collected from controls. Cells were stained using monoclonal antibodies. Flow cytometry assessed the fraction of cTfh (CD3+CD4+CXCR5+) and cTph (CD3+CD4+CXCR5-PD-1hi) cells.. Results: Flow cytometric analysis showed increased fractions of activated cTfh subsets including ICOS+ and ICOS+PD-1+ expressing cells, in patients compared to controls. Biologic blocking of IL-17A diminished the cTfh population. Furthermore, ICOS+ and ICOS+PD-1+ sub-populations were also inhibited. Finally, the cTph cell fraction significantly decreased after three months of successful treatment with biologics. Conclusion: Early anti-IL-17-mediated clinical remission in Ps is associated with decreased cTfh and cTph cell subpopulations.
Subject(s)
Biological Products , Interleukin-17 , Psoriasis , Humans , Psoriasis/immunology , Psoriasis/drug therapy , Male , Female , Interleukin-17/metabolism , Interleukin-17/antagonists & inhibitors , Adult , Middle Aged , Biological Products/therapeutic use , Biological Products/pharmacology , T Follicular Helper Cells/immunology , T-Lymphocytes, Helper-Inducer/immunology , T-Lymphocytes, Helper-Inducer/metabolism , T-Lymphocytes, Helper-Inducer/drug effects , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , T-Lymphocyte Subsets/drug effectsABSTRACT
Follicular helper T (TFH) cells mediate germinal center reactions to generate high affinity antibodies against specific pathogens, and their excessive production is associated with the pathogenesis of systemic autoimmune diseases such as systemic lupus erythematosus (SLE). ETV5, a member of the ETS transcription factor family, promotes TFH cell differentiation in mice. In this study, we examined the role of ETV5 in the pathogenesis of lupus in mice and humans. T cell-specific deletion of Etv5 alleles ameliorated TFH cell differentiation and autoimmune phenotypes in lupus mouse models. Further, we identified SPP1 as an ETV5 target that promotes TFH cell differentiation in both mice and humans. Notably, extracellular osteopontin (OPN) encoded by SPP1 enhances TFH cell differentiation by activating the CD44-AKT signaling pathway. Furthermore, ETV5 and SPP1 levels were increased in CD4+ T cells from patients with SLE and were positively correlated with disease activity. Taken together, our findings demonstrate that ETV5 is a lupus-promoting transcription factor, and secreted OPN promotes TFH cell differentiation.
Subject(s)
Cell Differentiation , Lupus Erythematosus, Systemic , Osteopontin , Transcription Factors , Animals , Lupus Erythematosus, Systemic/immunology , Lupus Erythematosus, Systemic/metabolism , Lupus Erythematosus, Systemic/genetics , Lupus Erythematosus, Systemic/pathology , Osteopontin/metabolism , Osteopontin/genetics , Mice , Humans , Transcription Factors/metabolism , Transcription Factors/genetics , DNA-Binding Proteins/metabolism , DNA-Binding Proteins/genetics , T-Lymphocytes, Helper-Inducer/immunology , T-Lymphocytes, Helper-Inducer/metabolism , T Follicular Helper Cells/immunology , T Follicular Helper Cells/metabolism , Female , Disease Models, Animal , Mice, KnockoutABSTRACT
Breast cancer (BC) continues to be the malignancy with the highest diagnosis rate worldwide. Between 15 % and 30 % of BC patients show overexpressed human epidermal growth factor receptor 2 (HER2), which is linked to poor clinical results in terms of invasiveness and recurrence risk. Passive immunity-based therapeutic approaches for treating HER2-enriched BC, are not effective and significant problems need to be tackled. Constructing multi-epitope vaccines is favored over single-epitope vaccines due to its ability to induce immunity against a variety of antigenic targets which will improve the efficacy of the vaccine. The current study describes a multi-epitope vaccine from HER2 protein against HER2-positive BC using several immunoinformatic techniques to achieve a potent and durable immune response. Nine Cytotoxic T lymphocytes (CTL) and five Helper T lymphocytes (HTL) epitopes were predicted and validated from HER2 protein using in silico tools. The expressed protein of the designed vaccine is predicted to be highly thermostable with better solubility. The predicted vaccine 3D structure was validated by ProSA servers and by the ERRAT server. Molecular docking analysis revealed a high binding affinity and stability of the designed vaccine with MHCI and TLR-2, 4, 7, and 9 receptors. The analysis of the C-ImmSim server revealed that the novel vaccine construct had the ability to elicit robust anti-cancerous innate, humoral, and cell-mediated immune responses. The vaccine can be a suitable option for HER2-positive BC patients and other patients with HER2-positive cancers to evoke immune responses. However, in vitro and in vivo experiments are needed to assess its effectiveness and safety.
Subject(s)
Breast Neoplasms , Cancer Vaccines , Epitopes, T-Lymphocyte , T-Lymphocytes, Cytotoxic , Female , Humans , Breast Neoplasms/immunology , Breast Neoplasms/therapy , Cancer Vaccines/immunology , Computer Simulation , Epitopes, T-Lymphocyte/immunology , Molecular Docking Simulation , Receptor, ErbB-2/immunology , Receptor, ErbB-2/metabolism , T-Lymphocytes, Cytotoxic/immunology , T-Lymphocytes, Helper-Inducer/immunologyABSTRACT
The development of an effective humoral response to pathogens and immunogens is a multiphase biological process, which is mediated by the coordinated function of specialized immune cell types in secondary lymphoid organs and particularly in T cell and follicular areas. More specifically, within the follicular/germinal center area, the orchestrated interplay between B cells, follicular helper CD4 T cells (Tfh), and stromal cells triggers a cascade of immune reactions leading to the development of memory B cells and plasma cells able to generate effective, antigen-specific antibodies. The role of Tfh cells in this process is critical. Given the need for vaccines capable to induce antibodies of high affinity, neutralizing activity, and durability, understanding the cellular and molecular mechanisms regulating Tfh cell development is of great importance. Here, we describe novel approaches for the comprehensive understanding of these cells and possible implications for future studies in vaccine development and the understanding of the pathogenesis of relevant diseases.
Subject(s)
T Follicular Helper Cells , Humans , T Follicular Helper Cells/immunology , Germinal Center/immunology , Germinal Center/cytology , B-Lymphocytes/immunology , T-Lymphocytes, Helper-Inducer/immunology , T-Lymphocytes, Helper-Inducer/metabolism , Cell Differentiation/immunologyABSTRACT
IgG4-related disease (IgG4-RD) is a recently described autoimmune disorder characterized by elevated serum IgG4 levels and tissue infiltration of IgG4+ plasma cells in multiple organ systems. Recent advancements have significantly enhanced our understanding of the pathological mechanism underlying this immune-mediated disease. T cell immunity plays a crucial role in the pathogenesis of IgG4-RD, and follicular helper T cells (Tfh) are particularly important in germinal center (GC) formation, plasmablast differentiation, and IgG4 class-switching. Apart from serum IgG4 concentrations, the expansion of circulating Tfh2 cells and plasmablasts may also serve as novel biomarkers for disease diagnosis and activity monitoring in IgG4-RD. Further exploration into the pathogenic roles of Tfh in IgG4-RD could potentially lead to identifying new therapeutic targets that offer more effective alternatives for treating this condition. In this review, we will focus on the current knowledge regarding the pathogenic roles Tfh cells play in IgG4-RD and outline potential therapeutic targets for future clinical intervention.
Subject(s)
Germinal Center , Immunoglobulin G4-Related Disease , Immunoglobulin G , T Follicular Helper Cells , Humans , Immunoglobulin G4-Related Disease/immunology , Immunoglobulin G4-Related Disease/diagnosis , Immunoglobulin G4-Related Disease/therapy , T Follicular Helper Cells/immunology , Animals , Immunoglobulin G/immunology , Germinal Center/immunology , Plasma Cells/immunology , T-Lymphocytes, Helper-Inducer/immunology , BiomarkersABSTRACT
The two primary forms of inflammatory disorders of the small intestine andcolon that make up inflammatory bowel disease (IBD) are ulcerative colitis (UC) and Crohn's disease (CD). While ulcerative colitis primarily affects the colon and the rectum, CD affects the small and large intestines, as well as the esophagus,mouth, anus, andstomach. Although the etiology of IBD is not completely clear, and there are many unknowns about it, the development, progression, and recurrence of IBD are significantly influenced by the activity of immune system cells, particularly lymphocytes, given that the disease is primarily caused by the immune system stimulation and activation against gastrointestinal (GI) tract components due to the inflammation caused by environmental factors such as viral or bacterial infections, etc. in genetically predisposed individuals. Maintaining homeostasis and the integrity of the mucosal barrier are critical in stopping the development of IBD. Specific immune system cells and the quantity of secretory mucus and microbiome are vital in maintaining this stability. Th22 cells are helper T lymphocyte subtypes that are particularly important for maintaining the integrity and equilibrium of the mucosal barrier. This review discusses the most recent research on these cells' biology, function, and evolution and their involvement in IBD.
Subject(s)
Inflammatory Bowel Diseases , Humans , Animals , Inflammatory Bowel Diseases/immunology , T-Lymphocytes, Helper-Inducer/immunology , Intestinal Mucosa/immunology , Intestinal Mucosa/microbiologyABSTRACT
The pig is emerging as a physiologically relevant biomedical large animal model. Delineating the functional roles of porcine adaptive T-lymphocyte subsets in health and disease is of critical significance, which facilitates mechanistic understanding of antigen-specific immune memory responses. We identified a novel T-helper/memory lymphocyte subset in pigs and performed phenotypic and functional characterization of these cells under steady state and following vaccination and infection with swine influenza A virus (SwIAV). A novel subset of CD3+CD4lowCD8α+CD8ß+ memory T-helper cells was identified in the blood of healthy adult pigs under homeostatic conditions. To understand the possible functional role/s of these cells, we characterized the antigen-specific T cell memory responses by multi-color flow cytometry in pigs vaccinated with a whole inactivated SwIAV vaccine, formulated with a phytoglycogen nanoparticle/STING agonist (ADU-S100) adjuvant (NanoS100-SwIAV). As a control, a commercial SwIAV vaccine was included in a heterologous challenge infection trial. The frequencies of antigen-specific IL-17A and IFNγ secreting CD3+CD4lowCD8α+CD8ß+ memory T-helper cells were significantly increased in the lung draining tracheobronchial lymph nodes (TBLN) of intradermal, intramuscular and intranasal inoculated NanoS100-SwIAV vaccine and commercial vaccine administered animals. While the frequencies of antigen-specific, IFNγ secreting CD3+CD4lowCD8α+CD8ß+ memory T-helper cells were significantly enhanced in the blood of intranasal and intramuscular vaccinates. These observations suggest that the CD3+CD4lowCD8α+CD8ß+ T-helper/memory cells in pigs may have a protective and/or regulatory role/s in immune responses against SwIAV infection. These observations highlight the heterogeneity and plasticity of porcine CD4+ T-helper/memory cells in response to respiratory viral infection in pigs. Comprehensive systems immunology studies are needed to further decipher the cellular lineages and functional role/s of this porcine T helper/memory cell subset.
Subject(s)
Influenza Vaccines , Orthomyxoviridae Infections , Swine Diseases , Animals , Swine/immunology , Influenza Vaccines/immunology , Orthomyxoviridae Infections/immunology , Orthomyxoviridae Infections/veterinary , Orthomyxoviridae Infections/prevention & control , Swine Diseases/immunology , Swine Diseases/virology , Swine Diseases/prevention & control , T-Lymphocytes, Helper-Inducer/immunology , Respiratory System/immunology , Respiratory System/virology , Lymphoid Tissue/immunology , Immunologic Memory , Memory T Cells/immunology , T-Lymphocyte Subsets/immunology , Influenza A virus/immunology , Vaccination/veterinaryABSTRACT
Inside germinal centers (GCs), antigen-specific B cells rely on precise interactions with immune cells and strategic localization between the dark and light zones to clonally expand, undergo affinity maturation, and differentiate into long-lived plasma cells or memory B cells. Follicular helper T (Tfh) cells, the key gatekeepers of GC-dependent humoral immunity, exhibit remarkable dynamic positioning within secondary lymphoid tissues and rely on intercellular interactions with antigen-presenting cells (APCs) during their differentiation and execution of B-cell-facilitating functions within GCs. In this review, we briefly cover the transcriptional regulation of Tfh cell differentiation and function and explore the molecular mechanisms governing Tfh cell motility, their interactions with B cells within GCs, and the impact of their dynamic behavior on humoral responses.