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

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 L-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.