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, 2345). 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 2345, 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 2345, 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.