A novel pro-survival and proliferation-inducing role for CCR4:TARC interaction in chronic lymphocytic leukemia (CLL) B cells

CLL is a lymphoproliferative disorder characterized by an accumulation of CD5+ B cells. Somatic mutation of Ig V genes and cell surface CD38 expression by CLL cells stratifies cases into clinically distinct subgroups. CLL cells are likely sustained by the stimulation via BCR, TLR, and cytokine/chemokine:ligand interactions. Here we report on CCR4 expression and function in CLL. Cases with high numbers of CD38+ cells (≥30%) showed significantly higher percentages of CCR4-expressing cells (52.8 ± 5.2; p< 0.01) than counterparts with low numbers of CD38+ cells (<30%) (33.7 ± 5.3). Among CD38+ clones, those with mutated Ig V genes exhibited more CCR4-expressing cells than those with unmutated Ig V genes (p< 0.01). CCR4 molecules were functional as defined by proximal events (significant increases in phosphorylation of Btk and STAT5 in response to varying doses of TARC, specific decreases in surface CCR4 expression, and, migratory responses to TARC). Among its downstream effects, TARC alone rescued 25-60% of CCR4+ CLL cells from apoptosis. Simultaneously TARC induced proliferation of CLL cells in a dose-dependent manner. BCR crosslinking, TLR-9 agonists, T cell help, and CD38:CD31 interactions increased density of CCR4, likely facilitating ligand-mediated effects. Taken together, these findings suggest an important and novel role for CCR4:TARC interaction in promoting CLL cell survival and proliferation downstream of several triggering molecules.