title: Chronic lymphocytic leukaemia cells drive the global CD4+ T cell repertoire towards a regulatory phenotype and leads to the accumulation of CD4+ forkhead box P3+ T cells.
abstract: Advanced chronic lymphocytic leukaemia (CLL) is associated with profound immunodeficiency, including changes in T regulatory cells (T(regs)). We determined the pattern of expression of forkhead box P3 (FoxP3), CD25, CD27 and CD127 and showed that the frequency of CD4+ FoxP3+ T cells was increased in CLL patients (12% versus 8% in controls). This increase was seen only in advanced disease, with selective expansion of FoxP3-expressing cells in the CD4+ CD25(low) population, whereas the number of CD4+ CD25(high) FoxP3+ cells was unchanged. CD4+ CD25(low) cells showed reduced expression of CD127 and increased CD27, and this regulatory phenotype was also seen on all CD4 T cells subsets in CLL patients, irrespective of CD25 or FoxP3 expression. Incubation of CD4+ T cells with primary CLL tumours led to a sixfold increase in the expression of FoxP3 in CD4+ CD25- T cells. Patients undergoing treatment with fludarabine demonstrated a transient increase in the percentage of CD4+ FoxP3+ T cells, but this reduced to normal levels post-treatment. This work demonstrates that patients with CLL exhibit a systemic T cell dysregulation leading to the accumulation of CD4+ FoxP3+ T cells. This appears to be driven by interaction with malignant cells, and increased understanding of the mechanisms that are involved could provide novel avenues for treatment.
authors: School of Cancer Sciences, University of Birmingham, Birmingham, UK.
authors: K P
authors: KP
authors: Piper
authors: M
authors: M
authors: Karanth
authors: A
authors: A
authors: McLarnon
authors: E
authors: E
authors: Kalk
authors: N
authors: N
authors: Khan
authors: J
authors: J
authors: Murray
authors: G
authors: G
authors: Pratt
authors: P A H
authors: PA
authors: Moss
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D018920:Coculture Techniques; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000096:biosynthesis*; D006801:Humans; D056747:Immunomodulation; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis; D053699:Interleukin-7 Receptor alpha Subunit / Q000096:biosynthesis; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D018655:Lymphocyte Count; D008875:Middle Aged; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000096:biosynthesis; D014740:Vidarabine / Q000031:analogs & derivatives / Q000627:therapeutic use
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D053645:Interleukin-2 Receptor alpha Subunit; D053699:Interleukin-7 Receptor alpha Subunit; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D014740:Vidarabine; C024352:fludarabine