The defects underlying impaired T-cell immunity in chronic lymphocytic leukaemia: the impact of lenalidomide

Abstract

CLL T cells exhibit functional defects and alterations in gene expression that show similarities to exhausted T cells in chronic viral infections. It is unclear whether CLL T cells are truly exhausted, or whether these defects are restricted to expanded populations of CMV specific cells. The phenotype and function of T cells from CLL patients was compared to age- and CMV-serostatus-matched controls. There were an increased proportion of effector T cells in CLL patients and CMV-seropositive individuals. CD8+ and CD4+ T cells from CLL patients had increased expression of exhaustion markers CD160 and CD244 irrespective of CMV-serostatus, whereas increased PD1 expression on CD8+ T cells was limited to CMV-seronegative patients. CLL CD8+ T cells also showed defects in proliferation and cytotoxicity irrespective of CMV-serostatus, with the cytolytic defect caused by impaired granzyme packaging into vesicles and non-polarized degranulation. In contrast to virally-induced exhaustion, CLL T cells had increased expression of TBET and increased interferon-γ production, but normal IL-2 production. As lenalidomide repairs the functional and phenotypic defects associated with T-cell exhaustion, the effect of this agent on the gene expression profiles of lymphocyte subsets from CLL patients and healthy controls was investigated. Lenalidomide induced the expression of genes involved in cytoskeletal signalling, lymphocyte activation, and proliferation. In particular, lenalidomide up-regulated the expression of several genes involved in tight junction signalling, a pathway that is potentially involved in lymphocyte motility, immune synapse formation, and transendothelial migration. This pathway was down-regulated in T cells from CLL patients, but, intriguingly, was up-regulated in CLL cells compared with healthy B cells. This pathway is known to be negatively regulated by a phosphatase, PP2A. Treatment of CLL cells and T cells with the PP2A inhibitor okadaic acid mimicked the effect of lenalidomide. In conclusion, CLL T cells exhibit features of pseudo-exhaustion irrespective of CMV serostatus. Lenalidomide up-regulates tight junction signalling, which is down-regulated in CLL T cells. Inhibition of PP2A is implicated in the mechanism of action of lenalidomide on T cells.