Endogenous Expression of the Human CD83 Attenuates EAE Symptoms in Humanized Transgenic Mice and Increases the Activity of Regulatory T Cells

Abstract

The CD83 is a type I membrane protein and part of the immunoglobulin superfamily of receptors. CD83 is involved in the regulation of antigen presentation and dendritic cell dependent allogeneic T cell proliferation. A soluble form of CD83 inhibits dendritic cell maturation and function. Furthermore, CD83 is expressed on activated B cells, T cells, and in particular on regulatory T cells. Previous studies on murine CD83 demonstrated this molecule to be involved in several immune-regulatory processes, comprising that CD83 plays a key role in the development und function of different immune cells. In order to get further insights into the function of the human CD83 and to provide preclinical tools to guide the function of CD83/sCD83 for therapeutic purposes we generated Bacterial Artificial Chromosomes (BAC) transgenic mice. BACs are excellent tools for manipulating large DNA fragments and are utilized to engineer transgenic mice by pronuclear injection. Two different founders of BAC transgenic mice expressing human CD83 (BAC-hCD83 tg mice) were generated and were examined for the hCD83 expression on different immune cells as well as both the in vitro and in vivo role of human CD83 (hCD83) in health and disease. Here, we found the hCD83 molecule to be present on activated DCs, B cells and subtypes of CD4 + T cells. CD8 + T cells, on the other hand, showed almost no hCD83 expression. To address the function of hCD83, we performed in vitro mixed lymphocyte reactions (MLR) as well as suppression assays and we used the in vivo model of experimental autoimmune encephalomyelitis (EAE) comparing wild-type and hCD83-BAC mice. Results herein showed a clearly diminished capacity of hCD83-BAC-derived T cells to proliferate accompanied by an enhanced activation and suppressive activity of hCD83-BAC-derived Tregs. Furthermore, hCD83-BAC mice were found to recover faster from EAE-associated symptoms than wild-type mice, encouraging the relevance also of the hCD83 as a key molecule for the regulatory phenotype of Tregs in vitro and in vivo .

The CD83 Molecule – An Important Immune Checkpoint

“…Consequently, these cells acquired immunomodulatory functions and efficiently suppressed effector T cell-mediated immune responses in vitro as well as in vivo (35). Moreover, CD4 + Foxp3 + T cells derived from BAC-transgenic mice expressing murine and human CD83 simultaneously, displayed an enhanced activated phenotype accompanied by an increased suppressive capacity in comparison to wt cells (39). The essential function of cell intrinsic CD83 expression in Tregs has been reported by studies of tissue specific conditional knockout (cKO) mice, in which CD83 is exclusively ablated in Foxp3 + Tregs.…”

“…Understanding the effects of specific immune modulating interventions can elucidate definitive molecular or cellular checkpoints of the complex inflammatory networks which modulate autoimmune diseases. Given the important role of CD83 for immune responses to non-self, it is not surprising that there are several reports of CD83 being involved in autoimmune processes (38,39,55,(97)(98)(99)(100)(101)(102)(103)(104)(105)(106)(107)(108)(109)(110). A recent report summarized immune-modulating functions of sCD83 therapy in models of multiple sclerosis, autoimmune uveitis and systemic lupus erythematosus (3).…”

Integrin α4β1/VCAM-1 Interaction Evokes Dynamic Cell Aggregation Between Immune Cells and Human Lung Microvascular Endothelial Cells at Infectious Hemolysis

“…Intriguingly, vascular cell adhesion molecule 1 (VCAM-1), known to be an endothelial ligand for integrin α4β1 that could mediate the adhesion of lymphocytes, monocytes, eosinophils, and basophils to vascular endothelium, was also increased in the filtered L-sup. (Zinser et al, 2019), mo-DCs with LPS pretreated RBCs significantly induced CD4 T cell proliferation (Figure 4B). To elucidate a mechanism responsible for the CD4 T cell activation, the NF-κB Reporter kit designed for monitoring the activity of the NF-κB signaling pathway in the cultured cells was employed.…”

T and B Lymphocyte Transcriptional States Differentiate between Sensitized and Unsensitized Individuals in Alpha-Gal Syndrome

“…EGR1 regulates the expression of several genes critical for immune regulation, including CD44 , IL-2 , and TNF [ 39 , 40 ]. There was a significant upregulation of genes encoding MHC II molecules, such as HLA-DRB3 and HLA-DMA , intimately involved in antigen presentation, as well as CD83 , a surface receptor expressed on activated B and T cells [ 41 ] that can regulate antigen presentation.…”