Bcl-xL affects the development of functional CD4 Tregs
© BioMed Central Ltd 2010
Published: 23 July 2010
We read with great interest the article by Haque and colleagues  in a recent issue of Arthritis Research & Therapy. They hypothesized that co-transduction of CD4+ T cells with both forkhead box P3 transcription factor (FoxP3) and Bcl-xL will generate highly reactive regulatory T cells (Tregs) that can be used to prevent auto immune disease. The authors showed that the accumulation, persistence, and efficient 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 first 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  and because the results presented in their article confirm our previous studies [2–5], we think that it is important, scientifically and ethically, to acknowledge these data.
Our group has been studying systemic lupus erythematosus (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 . We showed that Bcl-xL was upregulated in CD4 Tregs of SLE-affected (NZBxNZW)F1 mice following treatment with the tolerogenic peptide . Bcl-xL played a suppressive role in the tolerized mice, as it inhibited the activation of T and B cells, and mediated the downregulating effects of hCDR1 on the production of the pathogenic cytokines interferon-gamma and interleukin-10 and the upregulating effects on the immunosuppressive cytokine transforming growth factor-beta (TGF-β). Furthermore, CD4 Tregs of the tolerized mice elicited the expression of BclxL in the effector CD4 cells, thus contributing to the amelioration of SLE manifestations . Although CD8 Tregs could not trigger the expression of Bcl-xL in effector CD4 cells, the former cells were essential for the optimal inhibitory function of CD4 Tregs . 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 (programmed death 1) . We showed that Bcl-xL also mediated the induction of CTLA-4 and TGF-β in effector CD4 cells by CD4 Tregs of the tolerized mice, thus explaining the inhibition of proliferation and the decreased activation of effector CD4 cells . These newly described roles of Bcl-xL may provide a novel mechanism of induction of CD4 Tregs. All together, our data [2–5], supported by those presented by Haque and colleagues , suggest that immunomodulation of Bcl-xL expression in T cells might be valuable for controlling and treating diseases that are affected by CD4 Tregs.
cytotoxic T lymphocyte antigen 4
forkhead box P3 transcription factor
systemic lupus erythematosus
transforming growth factor-beta
regulatory T cell.
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