Dataset Information

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-hCD83tg 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.

SUBMITTER: Zinser E

PROVIDER: S-EPMC6603205 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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

Zinser Elisabeth E Naumann Ronald R Wild Andreas B AB Michalski Julia J Deinzer Andrea A Stich Lena L Kuhnt Christine C Steinkasserer Alexander A Knippertz Ilka I

Frontiers in immunology 20190625

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 proces ...[more]

PMID: 31293592

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Project description:BackgroundStaphylococcus aureus can cause serious infections by secreting many superantigen exotoxins in "carrier" or "pathogenic" states. HLA DQ and HLA DR humanized mice have been used as a small animal model to study the role of two molecules during S. aureus infection. However, the contribution of HLA DP to S. aureus infection is unknown yet.MethodsIn this study, we have produced HLA DP401 and HLA DRA0101 humanized mice by microinjection of C57BL/6J zygotes. Neo-floxed IAβ+/- mice were crossbred with Ella-Cre and further crossbred with HLA DP401 or HLA-DRA0101 humanized mice. After several rounds of traditional crossbreeding, we finally obtained HLA DP401-IAβ-/- and HLA DRA-IAβ-/- humanized mice, in which human DP401 or DRA0101 molecule was introduced into IAβ-/- mice deficient in endogenous murine MHC class II molecules. A transnasal infection murine model of S. aureus pneumonia was induced in the humanized mice by administering 2 × 108 CFU of S. aureus Newman dropwise into the nasal cavity. The immune responses and histopathology changes were further assessed in lungs in these infected mice.ResultsWe evaluated the local and systemic effects of S. aureus delivered intranasally in HLA DP401-IAβ-/- and HLA DRA-IAβ-/- transgenic mice. S. aureus Newman infection significantly increased the mRNA level of IL 12p40 in lungs in humanized mice. An increase in IFN-γ and IL-6 protein was observed in HLA DRA-IAβ-/- mice. We observed a declining trend in the percentage of F4/80+ macrophages in lungs in HLA DP401-IAβ-/- mice and a decreasing ratio of CD4+ to CD8+ T cells in lungs in IAβ-/- mice and HLA DP401-IAβ-/- mice. A decreasing ratio of Vβ3+ to Vβ8+ T cells was also found in the lymph node of IAβ-/- mice and HLA DP401-IAβ-/- mice. S. aureus Newman infection resulted in a weaker pathological injury in lungs in IAβ-/- genetic background mice.ConclusionThese humanized mice will be an invaluable mouse model to resolve the pathological mechanism of S. aureus pneumonia and study what role DP molecule plays in S. aureus infection.

Dataset Information

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

Publications

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

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0.5

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