title: Enhanced formation and survival of CD4+ CD25hi 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.
authors.affiliation: Department of Hematology, Academic Medical Center, Amsterdam, The Netherlands. m.jak@amc.uva.nl
authors.forename: Margot
authors.initials: M
authors.lastname: Jak
authors.forename: Rogier
authors.initials: R
authors.lastname: Mous
authors.forename: Ester B M
authors.initials: EB
authors.lastname: Remmerswaal
authors.forename: René
authors.initials: R
authors.lastname: Spijker
authors.forename: Annelieke
authors.initials: A
authors.lastname: Jaspers
authors.forename: Adriana
authors.initials: A
authors.lastname: Yagüe
authors.forename: Eric
authors.initials: E
authors.lastname: Eldering
authors.forename: René A W
authors.initials: RA
authors.lastname: Van Lier
authors.forename: Marinus H J
authors.initials: MH
authors.lastname: Van Oers
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D053282:CD27 Ligand / Q000378:metabolism* / Q000502:physiology; D023201:CD40 Ligand / Q000378:metabolism; D016022:Case-Control Studies; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D019008:Drug Resistance, Neoplasm; D020869:Gene Expression Profiling; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism / Q000473:pathology*; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D053282:CD27 Ligand; C498702:PMAIP1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D023201:CD40 Ligand