Abstract
The vast majority of Foxp3 regulatory T cells (Treg) exhibits constitutive expression of CD25 (IL-2Rα), which allows the constitution of the high affinity IL-2Rαβγ receptor, ensuring efficient IL-2 binding by Treg. Maintenance of CD25 expression at Treg surface depends on both cell intrinsic factors and environmental stimuli such as IL-2 itself. Whether other factors can participate to maintenance of CD25 expression in vivo is at present unknown. In the present work we demonstrated that IL-7, a gamma-chain cytokine exerting a crucial role in T cell development and homeostasis, is able and necessary to sustain the expression of high levels of CD25 at Treg surface. We demonstrated that, during in vitro cultures performed in the absence of IL-2, IL-7 is able to sustain CD25 expression at Treg surface through a transcriptional mechanism. By studying mice in which IL-7 signaling is either genetically impaired or increased and by employing adoptive transfer murine models, we demonstrated that IL-7 is necessary for sustained expression of CD25 at Treg surface in vivo. To ascertain the biological impact of IL-7 mediated modulation of CD25 expression, we demonstrated that IL-7 modulation of CD25 expression at Treg surface affected their ability to efficiently bind IL-2 and transduce IL-2 signaling. Finally, we demonstrated that IL-7 dependent modulation of CD25 associated with potentiated IL-2 induced expansion of Treg in vivo. Collectively, our results identify IL-7 as a necessary factor contributing to sustained CD25 expression at Treg surface in vivo thereby affecting their ability to efficiently react to IL-2.
Highlights
CD4+FOXP3+ T cells represent a subset of CD4+ T cells crucial for immuneresponses regulation and prevention of immune-pathology [1]
In order to assess the possibility that CD25 expression on Treg cells can be dynamically regulated by IL-7 availability, we FACS sorted CD4+ FOXP3/GFP+ lymph nodes and spleen cells from FOXP3/GFP mice and cultured them overnight with medium alone or in the presence of IL-7 or IL-2 as control
We found a significant increase in proportions of live Treg cells in cells cultured in the presence of either IL-7 or IL-2 compared to cells cultured in medium alone
Summary
CD4+FOXP3+ T cells represent a subset of CD4+ T cells crucial for immuneresponses regulation and prevention of immune-pathology [1]. Together with the beta chain CD122 and the common gamma chain CD132, CD25 expression allows the constitution of the high affinity IL-2 receptor (IL-2Rabc). In accordance to their constitutive CD25 expression, Treg cells are sensitive to IL-2 signaling on which they are dependent for their development [3]–[6], their peripheral homeostasis [7]–[11], and their function [12]–[13]. Given the very limited amounts of IL-2 available in vivo at the steady state and during the first phases of immune responses, expression of the high affinity IL-2Rabc is essential for rapid cytokine binding and signal transduction by Treg, the absence of CD25 resulting in their impaired competitive fitness [3]
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