Cellular and Molecular Mechanisms in Immune Regulation

Dear Colleagues,

Vaccines and immunotherapies for infectious diseases and cancer are key components of modern medicine. The next generation of immune therapies will come from a better understanding of how the immune system interacts and is regulated by local tissues. In this Special Issue of Cells entitled “Cellular and Molecular Mechanisms in Immune regulation”, we will explore topics such as the regulation of T cell maintenance in the periphery and formation of immunological memory, the role of innate immune cells and fibroblasts in wound healing, cancer and autoimmune diseases, the regulation of inflammation and the immune response by nerve cells, and the role of innate lymphoid cells (ILCs) in the development of lymphoid tissues. We also welcome manuscripts showing how these processes can be manipulated by biological therapies, monoclonal antibodies, and CAR T cells for the treatment of infections, cancer, and autoimmune diseases.

Dr. Fábio Rinaldo Santori
Dr. Natalia B. Ivanova
Guest Editors

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• innate immunity
• dendritic cells
• macrophages
• T cells
• B cells
• cytokines
• immunotherapy

Title: The role of oxygen in metabolic programming of tolerogenic dendritic cells: tailoring in vitro generation and immune-modulatory function
Authors: Antonia Peter1, Tamara Traitteur1, Sara Tekavec1, Morgane Vermeulen1, Mats van Delen1, Amber Dams1, Hans de Reu1, Zwi Berneman1,2, Nathalie Cools1,2
Affiliation: 1Laboratory of Experimental Hematology, VAXINFECTIO, Faculty of Medicine and Health Sciences, University of Antwerp, Belgium 2Center for Cell Therapy and Regenerative Medicine, Antwerp University Hospital, Belgium
Abstract: PURPOSE A promising treatment approach for autoimmune diseases is to re-induce tolerance using tolerogenic dendritic cells (tolDCs). While the potential of tolDCs to downmodulate pro-inflammatory pathogenic responses in multiple sclerosis (MS) has been recognized, little is known about their mode of action and optimal culture conditions. Since metabolic pathways have been assigned a crucial role in shaping immune responses, we hypothesize that the immunoregulatory effect of tolDCs can be shaped by adjusting the microenvironment during the culture process. In doing so, we aim to increase the conversion rate of monocytes into tolDCs and ultimately optimize the manufacturing procedure. METHODS Human conventional DCs (convDCs) and tolDCs are generated from monocytes in the presence of IL-4 and GM-CSF and stimulated by adding the pro-inflammatory cytokines IL-1-beta, TNF-alpha, and PGE2. The tolerogenic phenotype of tolDCs is induced by 1,25(OH)2 vitamin D3 and confirmed by allo-MLR and flow cytometry. Next, we monitor metabolically relevant parameters, including oxygen (O2) consumption and lactate production, and assess the effect of different culture conditions such as O2 deprivation on the cells’ characteristics. RESULTS Our data show that tolDCs generated in the presence of 1,25(OH)2 vitamin D3 demonstrate reduced expression of the maturation markers CD80, CD83, and CD86 as compared to convDCs, and induce T-cell hyporesponsiveness in an allo-MLR. Additionally, tolDCs manifest significantly increased lactate production and O2 consumption as compared with convDCs. Furthermore, hypoxic culture conditions significantly decrease the viability and conversion rate of the cells, elicit reduced expression of identity marker CD209 and maturation markers (CD83, CD80, CD86, HLA-DR), and upregulate migration markers (CCR5, CCR7). Functional assays revealed a significantly enhanced migration capacity of tolDCs under hypoxia. In a hypoxic allo-MLR, no difference was observed in the IFN-gamma secretion of T cells between tolDCs and convDCs. However, phenotyping revealed differential expression of T cell exhaustion markers between the two. CONCLUSIONS Our observations suggest that tolDCs are metabolically different from convDCs. This may provide further insights into how tolDCs contribute to tolerance induction by metabolomic reprogramming. Furthermore, these findings might offer a deeper understanding of tolDC fate after patient administration, where O2 levels do not exceed 5 %. In summary, a better understanding of tolDC metabolism could lead to new ways of optimizing tolDC-based vaccines by increasing their potential to fight autoimmune diseases.

Title: circRNAs regulation and dysregulation in Multiple sclerosis
Authors: Matteo Floris; Maria Laura Idda; Valeria Lodde
Affiliation: Associate Professor - Medical Genetics Department of Biomedical Sciences University of Sassari (Italy)
Abstract: Introduction: Multiple sclerosis (MS) is a demyelinating autoimmune disease characterized by early onset and for which the interaction of genetic and environmental factors is crucial. Dysregulation of the immune system as well as myelinization-de-myelinization has been shown to correlate with changes in RNA including non-coding RNAs. Recently, circular RNAs (circRNAs), have emerged as a key player in the complex network of gene dysregulation associated with MS. Despite several efforts, the mechanisms driving circRNAs regulation and dysregulation in MS still need to be properly elucidated. Methods: Here we explore the panorama of circRNA expression in PBMCs purified from 5 newly diagnosed MS patients and 5 healthy controls (HC) using the Arraystar Human circRNAs microarray. Experimental validation was then carried out in a validation cohort and possible correlation with disease severity was tested. Results: We identified 64 differentially expressed circRNAs, 53 of which were downregulated in PBMCs purified from MS compared to HC. The discovery dataset was subsequently validated using qRT-PCR with an independent cohort of 20 RRMS patients and 20 HCs. We validated seven circRNAs differentially expressed in the RRMS group versus the HC group. hsa_circ_0000518, hsa_circ_0000517, hsa_circ_0000514, and hsa_circ_0000511 were significantly upregulated in the MS group, while hsa_circ_0018905, hsa_circ_0048764, and hsa_circ_0003445 were significantly downregulated; Among them, the expression level of hsa_circ_0018905 was significantly decreased in patients showing a higher level of disability and in progressive form of MS. Conclusion: We described the circRNAs expression profile of PBMCs in newly diagnosed MS patients and propose hsa_circ_0018905 as potential MS biomarker.

Title: Dual Challenges of Dengue Envelope Protein Domain 3 and Autoantibodies Trigger Apoptosis-Related Endothelial Damage and Hemorrhagic Pathogenesis in Mice
Author: Chang
Highlights: • Innovative Model: Our two-hit mouse model, using rEIII and anti-platelet auto-antibody, closely simulates dengue hemorrhagic fever (DHF) progression. • In Vivo Findings: rEIII and autoantibodies were shown to induce endothelial apoptosis, replicating DHF symptoms. • Therapeutic Potential: Our study highlights promising therapies targeting EIII binding, reducing ROS with NAC, and inhibiting apoptosis with caspase-3 inhibitors.