Prevention strategies differentially modulate the impact of cytomegalovirus replication on CD8+ T-cell differentiation in high-risk solid organ transplant patients

•In high-risk solid organ transplant patients both prophylaxis and pre-emptive therapy can be used.•Patients under pre-emptive therapy show a higher frequency of recurrent CMV episodes.•CMV recurrence is associated with a high expansion of late-differentiated CD8+ T cells with high functionality.•Potential beneficial and detrimental effects of this specific expansion are discussed.

The present study aimed to determine whether antiviral prevention strategies against cytomegalovirus (CMV) infection used in high-risk D+R- solid organ transplanted patients can modulate the impact of CMV replication on CD8+ T-cell differentiation. The different CD8+ T-cell subpopulations were measured at a single point when at least one year had elapsed since transplantation. A total of 68 D+R- patients were included, of which 33 underwent pre-emptive therapy and 35 received prophylaxis. Multivariate analysis showed that CMV replication was associated with the expansion of CD28Ö¾ EMRA CD8+ T cells in patients managed pre-emptively but not in patients under prophylaxis (21.4% vs. 3.6%). This finding is likely related to the higher frequency of CMV recurrence observed in patients under pre-emptive therapy compared to those under prophylaxis (75% vs. 14.3%; p < 0.001). In fact, multivariate analysis showed that having more than one replication episode was associated with a 17.2% increase (p = 0.001) in the percentage of CD28Ö¾ EMRA CD8+ T cells compared to “no episode” and with a 10.9% increase with respect to “single episodes” (p = 0.025). Additionally, patients with IFNγ response to CMV (QuantiFERON-CMV Reactive) had a higher percentage of late-differentiated CD8+ T cells than patients lacking this response. In summary, recurrent CMV replication in D+R- patients under pre-emptive therapy was associated with the expansion of CD28Ö¾ EMRA CD8+ T cells, which might have a short-term beneficial effect related to the high functionality of this T-cell subpopulation. Nevertheless, we cannot rule out that this accumulation might have a long-term detrimental effect related to immunosenescence and inflammation.