Letter | Open | Published:
Bcl-xL affects the development of functional CD4 Tregs
Arthritis Research & Therapyvolume 12, Article number: 405 (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.
Haque R, Lei F, Xiong X, Wu Y, Song J: FoxP3 and Bcl-xL cooperatively promote regulatory T cell persistence and prevention of arthritis development. Arthritis Res Ther. 2010, 12: R66-10.1186/ar2983.
Sharabi A, Zinger H, Zborowsky M, Sthoeger ZM, Mozes E: A peptide based on the complementarity-determining region 1 of an autoantibody ameliorates lupus by up-regulating CD4+CD25+ cells and TGF-beta. Proc Natl Acad Sci USA. 2006, 103: 8810-8815. 10.1073/pnas.0603201103.
Sharabi A, Luger D, Ben-David H, Dayan M, Zinger H, Mozes E: The role of apoptosis in the ameliorating effects of a CDR1-based peptide on lupus manifestations in a mouse model. J Immunol. 2007, 179: 4979-4987.
Sharabi A, Mozes E: The suppression of murine lupus by a tolerogenic peptide involves foxp3-expressing CD8 cells that are required for the optimal induction and function of foxp3-expressing CD4 cells. J Immunol. 2008, 181: 3243-3251.
Sharabi A, Lapter S, Mozes E: Bcl-xL is required for the development of functional regulatory CD4 cells in lupus-afflicted mice following treatment with a tolerogenic peptide. J Autoimmun. 2010, 34: 87-95. 10.1016/j.jaut.2009.06.002.
The authors declare that they have no competing interests.