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.
Highlights
Accumulated evidence suggests that both innate and adaptive immunity are involved in regulating inflammatory responses in diverse diseases including infection, autoimmunity and transplant rejection though precise mechanisms are still unclear [1]
The percentage of CD4+CD25+ T cells were analyzed in the spleen (Spln) and peripheral lymph nodes (LNs) by flow cytometry
By gating on the CD4+CD25+ T cells, we observed that the percentages of Tregs expressing CD62L+ (p < 0.005 and p < 0.0005, respectively; Figure 1C and Supplementary Figure 1B) but not CD73+ (Figure 1E and Supplementary Figure 1C) were significantly higher in PAR4ko compared to WT mice
Summary
Accumulated evidence suggests that both innate and adaptive immunity are involved in regulating inflammatory responses in diverse diseases including infection, autoimmunity and transplant rejection though precise mechanisms are still unclear [1]. Various molecular signals are capable of manipulating the function of Tregs including signaling through innate receptors such as Toll like receptors (TLRs) [9, 10] and anaphylatoxin receptors (C3aR/C5aR) [11, 12]. Signaling through these receptors downregulates FoxP3 expression which causes Tregs to adopt an effector T cell function [13, 14], causing autoimmunity [15, 16], or transplant rejection [17,18,19]. The precise mechanisms behind how these signaling pathways alter the function of Tregs are not fully understood, recent studies have suggested PTEN
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