Abstract
Regulatory T-cells (Tregs) are central for immune homeostasis and divided in thymus-derived natural Tregs and peripherally induced iTreg. However, while phenotype and function of iTregs are well known, a remarkable lack exists in knowledge about signaling mechanisms leading to their generation from naïve precursors in peripheral tissues. Using antigen specific naïve T-cells from mice, we investigated CD4+ CD25+ FoxP3- iTreg induction during antigen-specific T-cell receptor (TCR) stimulation with weak antigen presenting cells (APC). We show that early signaling pathways such as ADAM-17-activation appeared similar in developing iTreg and effector cells (Teff) and both initially shedded CD62-L. But iTreg started reexpressing CD62-L after 24 h while Teff permanently downmodulated it. Furthermore, between 24 and 72 hours iTreg presented with significantly lower phosphorylation levels of Akt-S473 suggesting lower activity of the PI3K/Akt-axis. This was associated with a higher expression of the Akt hydrophobic motif-specific phosphatase PHLPP1 in iTreg. Importantly, the lack of costimulatory signals via CD28 from weak APC was central for the development of regulatory function in iTreg but not for the reappearance of CD62-L. Thus, T-cells display a window of sensitivity after onset of TCR triggering within which the intensity of the PI3K/Akt signal controls entry into either effector or regulatory pathways.
Highlights
Following T-cell receptor (TCR) triggering, naıve T-cells have multiple possibilities into which type of effector phenotype they develop [1]
We previously demonstrated the induction of CD4+ CD25+ Foxp3- Treg cells from TCR-transgenic T-cells in vitro without lineage-modifying cytokines using TCR-triggers by weak antigen presenting cells
This was in contrast to type effector cells (Teff) generated from activating naıve T-cells by dendritic cells (DC) (TofDC) that showed permanent downregulation of CD62-L and effector functions of conventionally activated T-cells [16]
Summary
Following T-cell receptor (TCR) triggering, naıve T-cells have multiple possibilities into which type of effector phenotype they develop [1]. Current concepts describe the effector lineages, Th1, Th2, Th17, TFH and Treg and variations of these, where the status of ‘‘lineage’’ is still debated [2]. For these T-cell types master regulators have been identified driving the expression of lineageidentifying functions [3]. Tregs are a special lineage as they downregulate the activity of all other lines [5] and are divided into naturally occurring nTreg generated from T-cell precursors in the thymus and induced iTreg, which form in the periphery by conversion of effector T-cells or by appropriate de novo activation of naıve T-cells [6]. Tregs can be viewed based on their expression of the specific transcription factor FoxP3 as either FoxP3+ or FoxP32 Tregs [7,8]
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