Bcl-xL affects the development of functional CD4 Tregs

Letter

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, [2-5]). 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 [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 [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 [2-5], 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.

Abbreviations

CTLA-4: cytotoxic T lymphocyte antigen 4; FoxP3: forkhead box P3 transcription factor; SLE: systemic lupus erythematosus; TGF-β: transforming growth factor-beta; Treg: regulatory T cell.

Competing interests

The authors declare that they have no competing interests.

References

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. PubMed Abstract | BioMed Central Full Text | PubMed Central Full Text

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. PubMed Abstract | Publisher Full Text | PubMed Central Full Text

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 Abstract | Publisher Full Text

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 Abstract | Publisher Full Text

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. PubMed Abstract | Publisher Full Text

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