CD4 T cells to kiss off chemotherapy-resistant CMV?

Riddell and coworkers (Science. 1992;257:238-241) have shown that infusions of donor CD8 T cells with specificity for cytomegalovirus (CMV) can prevent viremia and clinical complications in patients undergoing allogeneic stem cell transplantation. In this issue, Einsele and colleagues (page 3916) report results following the infusion of donor T-cell lines for therapeutic intervention in the setting of chemotherapy-resistant CMV infection. A single infusion of T cells resulted in the clearing of CMV viremia in 5 of 7 patients, and a second infusion was associated with resolution of viremia in an additional patient, so that 6 of 7 patients had resolution of CMV. These studies extend previous studies because they suggest T-cell infusions comprising predominantly the CD4 subset may be efficient for the control of CMV viremia in immunosuppressed patients. It is also clear that CD8 cytotoxic T cells are required for the control of CMV infection, and this study, along with others, illustrates the critical requirement for CD4 cells in the control of many chronic viral infections.

Adoptive transfer of T cells for control of infections with CMV and Epstein-Barr virus has documented efficacy in the setting of immunosuppression, and studies show promise for patients with HIV infection. But there are several issues to be resolved before this procedure becomes a routine therapy for patients with severe viral infections. First, more efficient culture systems will aid in the delivery of this therapy. In this study, 4 repetitive stimulations with antigen-presenting cells were carried out in vitro before sufficient cells were available for therapy. Second, recent studies indicate that naive T cells emigrating from the thymus undergo differentiation to activated T cells, central memory T cells, peripheral effector T cells, and peripheral memory T cells. It is likely that optimal infusions would consist predominantly of central memory T cells in the prophylactic setting, while in the therapeutic setting T-cell infusions should be biased toward peripheral effector cells and peripheral memory T cells. Advances in present culture techniques will be required in order to address this issue. Finally, it is sobering to note that, despite control of CMV viremia in 6 of 7 patients, 3 patients subsequently developed invasive aspergillosis or respiratory syncytial virus interstitial pneumonitis in this study. Therefore, a comprehensive approach to reconstitute immunity in immunosuppressed patients is required.