Teriflunomide induces Foxp3 expression in murine CD8 + T cells while IL-27 and retinoic acid exert a synergistic effect on the induction of CD39 expression on these cells.

Abstract

The purpose of this study was to verify the possibility of pharmacological induction of Foxp3 +CD25 +CD8 + and Foxp3 -CD103 +CD8 + T regulatory cells 'armed' with immunosuppressive molecules, i.e. CD39 and IL-10. To achieve this purpose, stimulated and unstimulated murine lymphocytes were exposed to IL-27, teriflunomide (TER) and all trans retinoic acid (ATRA). The study found that: (a) IL-27 induced CD39 expression on Foxp3 +CD25 +CD8 + T cells and the ability of CD103+Foxp3-CD8+ T cells to produce IL-10 as well as increasing the absolute number of IL-10 +CD103 +Foxp3 -CD8 + T cells; (b) TER induced Foxp3 expression in CD25+CD8+ T cells and CD103 expression on Foxp3 -CD8 + T cells as well as increasing the absolute number of Foxp3 +CD25 +CD8 + T cells; (c) ATRA induced the capacity of Foxp3 +CD25 +CD8 + T cells to produce IL-10. The following desired interactions were demonstrated between IL-27 and ATRA: (a) a strong synergistic effect with respect to increasing CD39 expression and the ability to produce IL-10 by Foxp3 +CD25 +CD8 + T cells; (b) a synergistic effect with respect to increasing the absolute count of CD39 +Foxp3 +CD25 +CD8 + T cells. The study revealed that TER abolished all these effects. Therefore, a combination of the tested agents did not induce the generation of Foxp3 +CD25 +CD8 + and Foxp3 -CD103+CD8+ T cells characterized by extensive CD39 expression and IL-10 production. Thus, in the context of the pharmacological induction of IL-10 +CD39 +Foxp3 +CD25 +CD8 + and IL-10 +CD103 +Foxp3 -CD8 + T cells, these findings strongly suggest that a combination of TER with IL-27 and/or ATRA does not provide any benefits over TER alone; moreover, such a combination may result in abolishing the desired effects exerted by IL-27 and/or ATRA.