Patients with B cell chronic lymphocytic leukaemia have an expanded population of CD4+perforin expressing T cells enriched for human cytomegalovirus specificity and an effector-memory phenotype

P>We have previously shown an expansion of cytotoxic antigen-experienced CD4+T cells (CTLs) that express perforin (PF) in the peripheral blood of patients with B cell chronic lymphocytic leukaemia (B-CLL). Increased frequencies of CD4+CTLs have since been attributed to chronic viral infections, particularly, human cytomegalovirus (HCMV). The present study examined the involvement of CD4+CTLs in responses to HCMV in B-CLL, and characterized their differentiation. We studied 36 HCMV seropositive (SP) and seronegative B-CLL patients and 20 healthy age-matched individuals. The HCMV reactivity of CD4+PF+ and CD4+PF- cells was determined by interferon-gamma expression, and expression of CD45RA and CCR7 was assessed by flow cytometry. Fluorescence in-situ hybridization was used to measure relative telomere lengths. CD4+PF+T cell expansion in B-CLL patients and controls was strongly associated with HCMV seropositivity. CD4+PF+ compared to CD4+PF- cells from SP B-CLL patients elicited major histocompatibility complex (MHC) class II-restricted responses to HCMV. CD4+PF+T cells from patients and controls were enriched with highly differentiated T-effector/memory (CCR7-) and revertant (CCR7-CD45RA+) phenotype. CD4+PF+T cells from B-CLL patients had shorter telomeres than CD4+PF-T cells, indicating an extensive replicative history. We conclude that persistent exposure to HCMV antigens in SP B-CLL patients leads to an expansion of the circulating MHC class II-restricted CD4+PF+T cell population with effector/memory phenotype.