Bcl-xL affects the development of functional CD4 Tregs

colleagues [1] in a recent issue of Arthritis Research & Th erapy. Th ey hypothesized that co-transduction of CD4 + T cells with both forkhead box P3 transcription factor (FoxP3) and Bcl-xL will gener ate highly reactive regulatory T cells (Tregs) that can be used to prevent auto immune disease. Th e authors showed that the accu mulation, persistence, and effi cient function of Tregs were attributable to the expression of Bcl-xL in CD4 Tregs. Indications for a potential role of Bcl-xL in the development of functional Tregs were fi rst described by our group, and the results of studies supporting this notion were published in numerous journals (for example , [2-5]). Because this information was not mentioned in the article by Haque and colleagues [1] and because the results presented in their article confi rm our previous studies [2-5], we think that it is important, scientifi cally and ethically, to acknowledge these data. Our group has been studying systemic lupus erythe ma-tosus (SLE) and developed a tolerogenic peptide, namely hCDR1, shown to ameliorate manifestations of the disease through several mechanisms of action, including the induction of CD4 Tregs [2]. We showed that Bcl-xL was upregulated in CD4 Tregs of SLE-aff ected (NZBxNZW)F1 mice follow ing treatment with the tolero genic peptide [3]. Bcl-xL played a suppressive role in the tolerized mice, as it inhibited the activation of T and B cells, and mediated the downregulating eff ects of hCDR1 on the production of the pathogenic cytokines interferon-gamma and interleukin-10 and the upregu-lating eff ects on the immunosuppressive cytokine transforming growth factor-beta (TGF-β). Furthermore, CD4 Tregs of the tolerized mice elicited the expression of Bcl-xL in the eff ector CD4 cells, thus contributing to the amelioration of SLE manifestations [3]. Although CD8 Tregs could not trigger the expression of Bcl-xL in eff ector CD4 cells, the former cells were essential for the optimal inhibitory function of CD4 Tregs [4]. Finally, we demonstrated that Bcl-xL played a role in inducing the regulatory/inhibitory molecules FoxP3, cytotoxic T lymphocyte antigen 4 (CTLA-4), and TGF-β and in repressing PD-1 (pro grammed death 1) [5]. We showed that Bcl-xL also mediated the induction of CTLA-4 and TGF-β in eff ector CD4 cells by CD4 Tregs of the tolerized mice, thus explaining the inhibition of proliferation and the decreased activation of eff ector CD4 cells [5]. Th ese newly described roles of Bcl-xL may provide a …