Cytomegalovirus replication is associated with enrichment of distinct γδ T cell subsets following lung transplantation: A novel therapeutic approach?

Stankovic, Sanda; Davey, Martin S.; Shaw, Evangeline M.; von Borstel, Anouk; Cristiano, Yvonne; Levvey, Bronwyn J.; Rossjohn, Jamie; Westall, Glen P.; Snell, Gregory I.; Brooks, Andrew G.; Sullivan, Lucy C.

BACKGROUND: Antiviral treatments to control cytomegalovirus (CMV) following lung transplantation (LTx) are associated with toxicity and antiviral resistance. Cellular immunotherapy with virus-specific cytotoxic T cells have yielded promising results but requires donor/recipient matching. Gamma delta (γδ) T cells are involved in antiviral immunity and can recognize antigens independently of major histocompatibility complex (MHC) and may not require the same level of matching. We assessed the phenotype of circulating γδ T cells following LTx to identify candidate populations for CMV immunotherapy. METHODS: Peripheral blood mononuclear cells (PBMC) were isolated from LTx recipients pre-transplant and at routine bronchoscopies post-LTx. Patients were stratified by risk of CMV disease into moderate risk (MR, recipient CMV seropositive, n=15) or high-risk (HR, recipient CMV seronegative/donor CMV seropositive, n=10). CMV replication was classified as PCR positive (>150 copies/ml) in blood and/or bronchoalveolar lavage within the first 18-months. The phenotype of γδ T cells was assessed by multi-colour flow cytometry and T cell receptor (TCR) sequences were determined deep sequencing. RESULTS: In HR LTx recipients with CMV replication, we observed striking phenotypic changes in γδ T cells, marked by an increase in the proportion of effector Vδ1+ γδ T cells expressing the activating natural killer cell receptor NKG2C. Moreover, we observed a remarkable increase in TCR diversity. CONCLUSION: NKG2C+ Vδ1+ γδ T cells were associated with CMV replication and may indicate their potential to control infection. As such, we propose they could be a potential target for cellular therapy against CMV.