Inverse Correlation of Vδ2-T-Cell Recovery with EBV Reactivation after Haploidentical Hematopoietic Stem Cell Transplantation

Background. Epstein-Barr virus (EBV) reactivation remains one of the life-threatening complications in recipients undergone haploidentical hematopoietic stem cell transplantation (haploHSCT). Reconstitution of traditional adaptive T lymphocytes is generally compromised at the early stage following transplantation, suggesting an important role of other immune effector cells in preventing from EBV reactivation. Our previous studies demonstrated that hampered recovery of CD4^-CD8^- T cells was associated with an increased occurrence of EBV reactivation after haploHSCT. γδ T is a dominant subgroup of CD4^-CD8^- T cells in the peripheral blood of healthy donors. Correlation of reconstituted γδ T cells with EBV reactivation has not been reported in the context of allogeneic HSCT.

Methods. This study prospectively included 132 adult patients with hematopoietic malignancy and receiving haploHSCT. Recovery characteristics of T-cell subpopulations were monitored by flow cytometry at 30, 60, and 90 days after haploHSCT. EBV-DNA loads in the peripheral blood were detected by real-time quantitative PCR before and after transplantation. Association between γδ T recovery and EBV reactivation were statistically analyzed.

Results. The median counts of peripheral Vδ2 cells were continuously lower in recipients with EBV reactivation compared with controls at 30, 60, and 90 days post-haploHSCT (P value was 0.006, <0.001, and 0.019, respectively). Whereas no significant association of Vδ1-cell recovery was found in the same setting. Landmark study further indicated that the cumulative incidence of EBV reactivation was significantly increased in recipients with lower day-30 Vδ2 cell counts. Cytotoxic effect of Vδ2 cells on EBV-targeted cells were further confirmed by in-vitro experiments. Consistently, recovered Vδ2-positive in contrast to Vδ2-negative γδ T cells were specifically activated upon EBV reactivation following haploHSCT. The incidences of CMV reactivation, bacteremia, invasive fungal infection (IFI), and II-IV and III-IV aGVHD were not significantly different between the groups with and without EBV reactivation (P > 0.1, respectively).

Conclusions. We clarified a specific association of recovered Vδ2 but not Vδ1 T cells with EBV reactivation following haploHSCT. These results may help better understand the intrinsic anti-EBV immunity after allogeneic HSCT and develop effective γδ T-cell-based therapy strategies.

Acknowledgments

This study is supported by the Foundation for Innovative Research Groups of the National Natural Science Foundation of China (Grant No. 81621001) and National Natural Science Foundation of China (Grant No. 81370666).