# New Insights Into Factors Shaping CMV‐Specific T‐Cell Polyfunctionality After Hematopoietic Cell Transplantation

## TL;DR

This study explores how different immunosuppressive drugs affect T-cell responses to CMV in patients who received hematopoietic cell transplants.

## Contribution

The study provides new insights into how timing and dosing of immunosuppressive agents influence CMV-specific T-cell polyfunctionality.

## Key findings

- Cyclosporine was associated with higher frequencies of polyfunctional T cells compared to tacrolimus.
- High-dose corticosteroids and prolonged MMF administration suppressed T-cell responses.
- Adjusting immunosuppression timing may improve management of CMV infections in transplant recipients.

## Abstract

Polyfunctional cytomegalovirus (CMV)‐specific T cells are critical for antiviral immunity in allogeneic hematopoietic cell transplantation (HCT) recipients. However, gaps remain in managing refractory CMV and optimizing virus‐specific cellular therapy (VST). We conducted a comparative analysis of how timing and dosing of immunosuppressive agents, including post‐transplant cyclophosphamide (PT‐Cy), corticosteroids, mycophenolate mofetil (MMF), and calcineurin inhibitors (CNIs), shape CMV‐specific T‐cell polyfunctionality. CD4+ and CD8+ T‐cell responses (IFN‐γ plus ≥ 1 functional marker) were assessed following pp65 stimulation within 100 days post‐HCT in the pre‐ and post‐letermovir era. Among 243 patients, 31% exhibited polyfunctional CD4+ and CD8+ responses. PT‐Cy did not significantly impair T‐cell functionality. Cyclosporine was associated with higher frequencies of polyfunctional T cells compared to tacrolimus, even at concentrations above the therapeutic range. Intermediate (≥ 0.5 mg/kg) and high‐dose (≥ 1 mg/kg) corticosteroids, especially within 2–4 weeks before testing, significantly suppressed T‐cell responses, though rapid tapering preserved function. Prolonged administration of MMF (≥ 2000 mg) diminished T‐cell polyfunctionality. These findings provide novel insights into the importance of timing and dosing of the immunosuppressive effects of PT‐Cy, corticosteroids, MMF and CNIs on CMV‐specific immunity. Adjusting immunosuppression in specific time windows may improve the management of refractory CMV infections and optimize VST in HCT recipients.