Enhanced formation and survival of CD4⁺ CD25^hi Foxp3⁺ T-cells in chronic lymphocytic leukemia

Abstract

Recently, it has been described that patients with chronic lymphocytic leukemia (CLL) have increased numbers of regulatory T (T_reg) cells. In the present study, we analysed the mechanism behind T_reg cells expansion in CLL. Neither analysis of the T-cell receptor repertoire nor CD45 isoform expression of T_reg cells from patients with CLL provided evidence for chronic (tumor) antigenic stimulation as a possible cause for T_reg cells expansion in CLL. We found evidence however for increased formation of T_reg cells via CD70 costimulation, because we observed that CD40 ligand activated CLL cells (which might be considered a model of lymph node CLL cells) strongly induced CD70-dependent formation of T_reg cells. Reverse transcription-multiplex ligation-dependent probe amplification assay expression analysis of 34 apoptosis-regulating genes showed that in comparison with other CD4⁺ T-cells, T_reg cells from both healthy individuals (HD) and patients with CLL had a high expression of pro-apoptotic Noxa and a low expression of anti-apoptotic Bcl-2. Strikingly, Bcl-2 levels of T_reg cells in patients with CLL were significantly higher than in HD. Finally, the different apoptotic profile resulted in differences at the functional level, because T_reg cells from patients with CLL were more resistant to drug-induced apoptosis than T_reg cells from HD. In conclusion, T_reg cells in CLL may accumulate both by increased formation, facilitated by CD27-CD70 interaction in the lymph node proliferation centres, and decreased sensitivity to apoptosis because of a shifted Noxa-Bcl-2 balance.

Keywords:

• Chronic lymphocytic leukemia
• regulatory T-cells
• apoptosis

Notes

There is an accompanying commentary that discusses this paper. Please refer to the issue Table of Contents.