Bcl-xL affects the development of functional CD4 Tregs

  • Amir Sharabi1, 2Email author and

    Affiliated with

    • Edna Mozes1

      Affiliated with

      Arthritis Research & Therapy201012:405

      DOI: 10.1186/ar3076

      Published: 23 July 2010

      We read with great interest the article by Haque and colleagues [1] 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, [25]). Because this information was not mentioned in the article by Haque and colleagues [1] and because the results presented in their article confirm our previous studies [25], 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 [2]. We showed that Bcl-xL was upregulated in CD4 Tregs of SLE-affected (NZBxNZW)F1 mice following treatment with the tolerogenic 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 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 [3]. 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 [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 (programmed death 1) [5]. 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 [5]. These newly described roles of Bcl-xL may provide a novel mechanism of induction of CD4 Tregs. All together, our data [25], supported by those presented by Haque and colleagues [1], 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


      Authors’ Affiliations

      Department of Immunology, The Weizmann Institute of Science
      Department of Internal Medicine B, The Tel Aviv Sourasky Medical Center


      1. 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.PubMedView Article
      2. 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.PubMedView Article
      3. 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.PubMed
      4. 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.PubMed
      5. 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.PubMedView Article


      © BioMed Central Ltd 2010