Notch activation on effector T cells increases their sensitivity to Treg cell‐mediated suppression through upregulation of TGF‐βRII expression

Abstract

Notch proteins play an important role in embryonic development and cell-fate decisions. Notch influences also the activation and differentiation of peripheral T cells. Here, we investigated whether Notch signaling modulates the response of effector T cells to regulatory T (Treg) cells. Pre-exposure of CD4 + CD25 − effector T cells to the Notch ligandsDelta-4 and Jagged-1, but not Delta-1, increases significantly effector T-cell sensitivity to Treg cell-mediated suppression through upregulation of TGF-βRII expression and increased levels of the phosphorylated form of the Smad 3 protein. This effect is relieved by anti-TGF-β Abs. We demonstrate that HES (hairy and enhancer of split), the main transcription factor downstream of Notch, induces strong transactivation of TGF-ßRII by binding the TGF-βRII promoter through its DNA-binding domain. Thus, the crosstalk between Notch and the TGF-β pathway leads to potentiation of the suppressive effect of Treg cells. Keywords:Immune regulation r Notch signaling r Regulatory T cells r TGF-βRII IntroductionThe Notch signaling system is conserved from Drosophila to humans and regulates cell differentiation, proliferation, and survival. Notch pathways play an important role in embryonic development, T-cell development and function, and in disease processes, including carcinogenesis and autoimmunity. In mammals there are four Notch receptors (1-4) and five Notch ligands (Jagged-1, Jagged-2, Delta-like 1 (DL-1), [1].Notch proteins exert their pleiotropic effects through the regulation of expression of various downstream genes, many of which require the interaction of Notch proteins with the DNA binding transcription factor CSL (also known as CBF1, Su(H), Correspondence: Prof. Yves Levy e-mail: yves.levy@hmn.aphp.fr and LAG-1) in order to form a short-lived nuclear transcription complex [2]. After engagement with its ligands, successive proteolytic events cause clipping of the Notch protein. The first is mediated by ADAM proteases and the second by the γ-secretase complex, in which presenilins (PS1 and PS2) constitute the active center of the enzyme complex. These proteolytic events ultimately release the intracellular domain of Notch (NICD). The formation of a complex of activated intracellular Notch protein and CSL converts CSL from a transcriptional repressor to a transcriptional transactivator. The genes encoding the HES (hairy and enhancer of split) family of basic helix-loop-helix proteins are Notch targets that are known to be essential for T-cell development and signaling. * These authors have contributed equally to this work.www.eji-journal.eu Eur. J. Immunol. 2012. 42: 1796-1803 Immunomodulation 1797In addition to influencing , Notch signaling has also been involved in the differentiation and expansion of regulatory T (Treg) cells [4]. Several reports have shown that the presence of Notch ligands, mostly of the Jagged family, can enhance Treg-cell differentiation and function in vitro [5]. For example, exposure of Treg cells to Jagged-2 expressed by hematopoietic progen...

IL-4/IL-13 Heteroreceptor Influences Th17 Cell Conversion and Sensitivity to Regulatory T Cell Suppression To Restrain Experimental Allergic Encephalomyelitis

“…Since Th1 and Th17 cells do not express the HR even in 13R +/+ mice, it is likely that the sensitivity to Treg suppression is guided by APCs whose function had been shaped by the HR (15, 16, 20, 21). It is possible that the interaction of naïve T cells with HR-conditioned APCs not only guides subset differentiation but also prompts expression of surface molecules that control the sensitivity of the effector to Treg suppression (41-44). In addition, since IL-21 has been shown to play a role in effector resistance to Treg suppression (45), it is possible that the differential sensitivity to Treg suppression among Th1 and Th17 cells is related to production of the cytokine by the latter not the former.…”

Microvascular Notch Signaling Is Upregulated in Response to Vascular Endothelial Growth Factor and Chronic Myocardial Ischemia

“…1, 2 More recent studies have even demonstrated Notch signaling to influence the activation and differentiation of T cells. 3 During both embryologic and adult vasculogenesis, Notch signaling is required for the differentiation of vascular smooth muscle cells from their precursor cells, 4 including controlling vascular smooth muscle cell differentiation in adult vascular disease following injury. 1, 5 There are 4 mammalian Notch receptors (Notch 1, 2, 3, and 4) as well as several Notch ligands (Jagged 1 and 2, Delta-like ligand [DLL] 1, 3, and 4).…”

Delta-like 1–Mediated Notch Signaling Enhances the In Vitro Conversion of Human Memory CD4 T Cells into FOXP3-Expressing Regulatory T Cells

“…Previous reports showed that Notch intracellular domain increases Smad3 protein at the transcriptional and posttranscriptional levels, as well as Smad nuclear translocation and its transactivation at promoter sites (18,28). Moreover, Notch ligands increase Treg suppressive function via the upregulation of TGF-b receptor expression and phosphorylation of Smad3 in effector T cells (19). We therefore hypothesize that the enhanced Smad2 and Smad3 phosphorylation we observed in the presence of DL1, an effect particularly evident in the absence of exogenous TGF-b, might occur via upregulation of TGF-b receptor and transcriptional/posttranscriptional modulation of Smad3 promoted by the ligand.…”

“…There is solid experimental data in mice demonstrating a crucial role for Notch signaling in the thymic generation of Treg, their peripheral expansion and function, as well as in the in vitro conversion of conventional T cells into iTreg (15)(16)(17)(18)(19). In humans, there is evidence suggesting a role of Notch signaling in thymic Treg development as well as in peripheral Treg expansion (20)(21)(22)(23), although the putative role of Notch signaling in iTreg conversion has never been formally assessed.…”