γδT cells elicited by CMV reactivation after allo-SCT cross-recognize CMV and leukemia

Human cytomegalovirus (CMV) infections and relapse of disease remain major problems after allogeneic stem cell transplantation (allo-SCT), in particular in combination with CMV-negative donors or cordblood transplantations. Recent data suggest a paradoxical association between CMV reactivation after allo-SCT and reduced leukemic relapse. Given the potential of V delta 2-negative gamma delta T cells to recognize CMV-infected cells and tumor cells, the molecular biology of distinct gamma delta T-cell subsets expanding during CMV reactivation after allo-SCT was investigated. V delta 2(neg) gamma delta T-cell expansions after CMV reactivation were observed not only with conventional but also cordblood donors. Expanded gamma delta T cells were capable of recognizing both CMV-infected cells and primary leukemic blasts. CMV and leukemia reactivity were restricted to the same clonal population, whereas other V delta 2(neg) T cells interact with dendritic cells (DCs). Cloned V delta 1 T-cell receptors (TCRs) mediated leukemia reactivity and DC interactions, but surprisingly not CMV reactivity. Interestingly, CD8 alpha alpha expression appeared to be a signature of gamma delta T cells after CMV exposure. However, functionally, CD8 alpha alpha was primarily important in combination with selected leukemia-reactive V delta 1 TCRs, demonstrating for the first time a co-stimulatory role of CD8 alpha alpha for distinct gamma delta TCRs. Based on these observations, we advocate the exploration of adoptive transfer of unmodified V delta 2(neg) gamma delta T cells after allo-SCT to tackle CMV reactivation and residual leukemic blasts, as well as application of leukemia-reactive V delta 1 TCR-engineered T cells as alternative therapeutic tools.