| Summary: | Our group has previously shown that CD4+Perforin (PFt T cells with cytotoxic potential are expanded in patients with B-CLL, accounting for up to 50% of CD4+ T cells in this disease. This study confinns the finding of increased percentages of CD4+PF+ T cells in a new cohort of B-CLL patients. However, the significance of this subset in B-CLL remains unclear. Evidence has accumulated for the potential role of CD4+ cytotoxic T cells in controlling cytomegalovirus (CMV). Therefore, a potential relationship between chronic CMV infection and CD4+PF+ T cell expansion in B-CLL was investigated. CMV seropositivity was found to be strongly associated with CD4+PF+ T cell expansion in both B-CLL patients and controls. This suggested that CD4+PF+ T cells from CMV seropositive (SP) patients and controls might contain clonally expanded populations of CMV-specific cells. To test this hypothesis, the CMV reactivity of CD4+PF+ and CD4+PF- T cells from B-CLL patients and controls was detennined using an intracellular cytokine staining flow cytometric assay. CD4+PF+ cells from untreated patients were enriched for CMV-reactive cells, as measured by . IFN-y production, compared to the CD4+PF- subset. In addition, the data indicated that CD4+ T cell immunity to CMV is dysregulated in B-CLL patients. CD4+PF+T cells from B-CLL patients are characterised by a highly differentiated CD2S-CD57+ phenotype. To further characterise the differentiation phenotype of these cells, the distribution of CD45RA and CCR7 was detennined on CD4+PF+ T cells from B-CLL patients and controls. CD4+PF+ T cells from B-CLL patients were both characterised by a highly differentiated T-effector memory TEM (CCRT) phenotype, but differed in the proportion of CD45RA expressing cells, which might reflect chronic T cell activation in the fonner group. ~inally, flowFISH analysis revealed that CD4+PF+ T cells had shorter telomeres compared CD4+PF- T cells in B-CLL patients, indicative of a more extensive replicative history. The results indicate that low, but persistent, antigenic exposure in CMVinfected individuals leads to the emergence of a CD4+PF+ T cell subset, characterised by a highly differentiated cell surface phenotype and shortened telomeres.
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