Abstract
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.
Highlights
The IL-7/IL-7 receptor (IL-7R) pathway is indispensable for B and T cell development
Using an immunosuppressive pre-clinical model with transiently inducible IL-7 hyperexpression, we verified inducibility and bioactivity of the transgenic IL-7 protein, demonstrated irregularities in immunoregulation following IL-7 hyperexpression, and showed that local islet IL-7 hyperexpression promoted CD4+ and CD8+ T cell infiltration leading to enhanced graft rejection
CD8+ T cells with a memory surface phenotype were preferentially expanded in an IL-7-rich environment
Summary
The IL-7/IL-7 receptor (IL-7R) pathway is indispensable for B and T cell development. The immune system relies on low concentrations of IL-7 to regulate T cell homeostasis and preserve T cell repertoire diversity [3, 4]. IL-7-associated homeostatic expansion is linked to inflammatory diseases, including graft-vs.-host-disease [5], rheumatoid arthritis [6], and multiple sclerosis [7]. An increased concentration of IL-7 and homeostatic expansion of T cells, including autoreactive T cells, is observed in patients with Type-1-Diabetes (T1D) who receive immunosuppression as part of transplantation therapy [12]. An increased IL-7 concentration abrogates the ability of human FOXP3+ regulatory T (Treg) cells to suppress autoreactive effector T cell activation in vitro [13]. IL-7 is, suggested to play a pivotal role in the development and recurrence of autoimmunity and graft failure
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
