Protease Activated Receptor 4 as a Novel Modulator of Regulatory T Cell Function

Abstract

Regulatory T cells (Tregs) are a subpopulation of T cells that maintain immunological tolerance. In inflammatory responses the function of Tregs is tightly controlled by several factors including signaling through innate receptors such as Toll like receptors and anaphylatoxin receptors allowing an effective immune response to be generated. Protease-activated receptors (PARs) are another family of innate receptors expressed on multiple cell types and involved in the pathogenesis of autoimmune disorders. Whether proteases are able to directly modulate Treg function is unknown. Here, we show using two complimentary approaches that signaling through PAR-4 influences the expression of CD25, CD62L, and CD73, the suppressive capacity, and the stability of Tregs , via phosphorylation of FoxO1 and negative regulation of PTEN and FoxP3. Taken together, our results demonstrate an important role of PAR4 in tuning the function of Tregs and open the possibility of targeting PAR4 to modulate immune responses.

The Effect of a Novel Serine Protease Inhibitor on Inflammation and Intestinal Permeability in a Murine Colitis Transfer Model

“…Taking a closer look at the possible mechanisms of action by which UAMC-00050 treatment ameliorated both intestinal inflammation and permeability, we first hypothesize a crosstalk between T cells and PARs as recently demonstrated for Treg cells and PAR4, where the activation of PAR4 on murine Tregs inhibits their function ( Peng et al, 2019 ). In this study, the transcription factor RORγt, which can be expressed by Treg cells, marginally increased at mRNA level upon UAMC-00050 treatment in T cell transfer colitis mice, whereas PAR4 mRNA expression showed a modest but statistically significant decrease.…”

Platelets differentially modulate CD4+ Treg activation via GPIIa/IIIb-, fibrinogen-, and PAR4-dependent pathways

“…Among others, PAR4 is known to be expressed on T cells [49]. Recent findings indicate a higher CD4 + Treg activity following PAR4 inhibition [28]. To determine whether the effect seen in our data is platelet dependent, we compared the effect of inhibition of PAR4 on CD4 + Treg activation in presence and absence of platelet-rich plasma (PRP) in vitro.…”

“…PAR4 on mice platelets is activated by thrombin in high concentrations and also through interaction with PAR3 in low concentrations [23,24]. PAR4 is present on platelets, endothelial cells [25], smooth muscle cells [26], and leukocytes, including T cells [27] and Tregs [28]. There seems to be a considerable similarity in the expression of PAR4 in humans and mice [22].…”

Molecular mechanism for impaired suppressive function of Tregs in autoimmune diseases: A summary of cell‐intrinsic and cell‐extrinsic factors

“…Tregs from PAR4 knockout mice displayed enhanced suppressive function of Tregs, which is consistent with the phenomenon observed from the WT Tregs treated with antagonist of PAR4. Analysis of the potential downstream pathway of PAR4 revealed a decreased phosphorylation of AKT‐Foxo1 and an enhanced phosphorylation of STAT5 and expression of PTEN in PAR4 knockout mice 40 . This suggested a PAR4 involved activation of PI3K‐AKT‐Foxo1 pathway to negatively regulate the expression of PTEN and the stability, and an inactivation of STAT5 pathway to co‐ordinate a negative regulation on the suppressive function of Tregs (Figure 3).…”