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

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.