CD8+γδ T Cells Are More Frequent in CMV Seropositive Bone Marrow Grafts and Display Phenotype of an Adaptive Immune Response

The role of gamma delta (gamma delta) T cells in human cytomegalovirus (HCMV) immune surveillance has been the focus of research interest for years. Recent reports have shown a substantial clonal proliferation of gamma delta T cells in response to HCMV, shedding light on the adaptive immune response of gamma delta T cells. Nevertheless, most efforts have focused on V delta 2(neg)gamma delta T cell subset while less attention has been given to investigate other less common gamma delta T cell subsets. In this regard, a distinct subpopulation of gamma delta T cells that expresses the CD8 coreceptor (CD8(+)gamma delta T cells) has not been thoroughly explored. Whether it is implicated in HCMV response and its ability to generate adaptive response has not been thoroughly investigated. In this study, we combined flow cytometry and immune sequencing of the TCR gamma-chain (TRG) to analyze in-depth bone marrow (BM) graft gamma delta T cells from CMV seropositive (CMV+) and CMV seronegative (CMV-) donors. We showed that the frequency of CD8(+)gamma delta T cells was significantly higher in CMV+ grafts compared to CMV- grafts (P<0.001). Further characterization revealed that CD8(+)gamma delta T cells from CMV+ grafts express V gamma 9(-) and preferentially differentiated from a naive to terminal effector memory phenotype (CD27(low/-)CD45RO(-)). In line with these findings, TRG immune sequencing revealed clonal focusing and reduced usage of the V gamma 9/JP gene segment in a CMV+ graft. Furthermore, CD8(+)gamma delta T cells showed an enhanced response to TCR/CD3 and cytokine stimulation in contrast to CD8(-)gamma delta T cells. We conclude that gamma delta T cells in BM grafts are reshaped by donor CMV serostatus and highlight the potential adaptive role of CD8(+)gamma delta T cells in HCMV immune response.