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Inducible IL-7 hyperexpression influences lymphocyte homeostasis and function and increases allograft rejection.
Front. Immunol. 10:742 (2019)
The IL-7/IL-7R pathway is essential for lymphocyte development and disturbances in the pathway can lead to immune deficiency or T cell mediated destruction. Here, the effect of transient hyperexpression of IL-7 was investigated on immune regulation and allograft rejection under immunosuppression. An experimental in vivo immunosuppressive mouse model of IL-7 hyperexpression was developed using transgenic mice (C57BL/6 background) carrying a tetracycline inducible IL-7 expression cassette, which allowed the temporally controlled induction of IL-7 hyperexpression by Dexamethasone and Doxycycline treatment. Upon induction of IL-7, the B220+ c-kit+ Pro/Pre-B I compartment in the bone marrow increased as compared to control mice in a serum IL-7 concentration-correlated manner. IL-7 hyperexpression also preferentially increased the population size of memory CD8+ T cells in secondary lymphoid organs, and reduced the proportion of CD4+Foxp3+ T regulatory cells. Of relevance to disease, conventional CD4+ T cells from an IL-7-rich milieu escaped T regulatory cell-mediated suppression in vitro and in a model of autoimmune diabetes in vivo. These findings were validated using an IL-7/anti-IL7 complex treatment mouse model to create an IL-7 rich environment. To study the effect of IL-7 on islet graft survival in a mismatched allograft model, BALB/c mice were rendered diabetic by streptozotocin und transplanted with IL-7-inducible or control islets from C57BL/6 mice. As expected, Dexamethasone and Doxycycline treatment prolonged graft median survival as compared to the untreated control group in this transplantation mouse model. However, upon induction of local IL-7 hyperexpression in the transplanted islets, graft survival time was decreased and this was accompanied by an increased CD4+ and CD8+ T cell infiltration in the islets. Altogether, the findings show that transient elevations of IL-7 can impair immune regulation and lead to graft loss also under immune suppression.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Allograft Rejection ; Immunosuppression ; Interleukin-7 ; Islet Transplantation ; Treg; Regulatory T-cells; Interleukin-7 Receptor; In-vivo; Mouse; Phenotype; Mice; Overexpression; Lymphopenia; Sensitivity; Activation
Language
english
Publication Year
2019
HGF-reported in Year
2019
ISSN (print) / ISBN
1664-3224
e-ISSN
1664-3224
Journal
Frontiers in Immunology
Quellenangaben
Volume: 10,
Article Number: 742
Publisher
Frontiers
Publishing Place
Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland
Reviewing status
Peer reviewed
Institute(s)
Institute of Pancreatic Islet Research (IPI)
POF-Topic(s)
90000 - German Center for Diabetes Research
Research field(s)
Helmholtz Diabetes Center
PSP Element(s)
G-502600-009
G-502600-006
G-502600-006
WOS ID
WOS:000464275400001
Scopus ID
85065400115
PubMed ID
31024566
Erfassungsdatum
2019-05-13