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

Sep 29, 2026

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Polyfunctional cytomegalovirus (CMV)-specific T cells are essential for antiviral control in allogeneic hematopoietic cell transplantation (HCT). A comparative analysis evaluates how timing and dosing of immunosuppressive regimens—including post-transplant cyclophosphamide (PT-Cy), corticosteroids, mycophenolate mofetil (MMF), and calcineurin inhibitors (CNIs)—shape CMV-specific polyfunctionality. In 243 patients assessed within 100 days after HCT using pp65 stimulation, 31% show polyfunctional CD4+ and CD8+ responses. PT-Cy shows no major functional impact, cyclosporine associates with higher polyfunctional frequencies than tacrolimus, corticosteroids suppress responses in a timing- and dose-dependent manner, and prolonged MMF reduces polyfunctionality, suggesting time-window optimization to improve refractory CMV management and VST outcomes.

LanguageEnglish

CategoryHealthcare

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Pages14

Reading Time35 min

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Abstract

Introduction

American Journal of Hematology RESEARCH ARTICLE OPEN ACCESS New Insights Into Factors Shaping CMV-Specific T-Cell Polyfunctionality After Hematopoietic Cell Transplantation Alicja Sadowska-Klasa1,2 | Fang Yun Lim1 | Hu Xie1 | Danniel Zamora1 | Terry Stevens-Ayers1 | Wendy M. Leisenring1,3 | Bradley C. Edmison1 | Stephen C. De Rosa1 | Marco Mielcarek1,3 | Michael Boeckh1,3 1Fred Hutchinson Cancer Center, Seattle, Washington, USA | 2Medical University of Gdansk, Gdansk, Poland | 3University of Washington, Seattle, Washington, USA Correspondence: Alicja Sadowska-Klasa ([asadowsk@fredhutch.org](asadowsk@fredhutch.org); [a.sadowska@gumed.edu.pl](a.sadowska@gumed.edu.pl)) | Michael Boeckh ([mboeckh@fredhutch.org](mboeckh@fredhutch.org)) Received: 28 September 2025 | Revised: 3 November 2025 | Accepted: 21 November 2025 Keywords: CMV-specific T cells | drug effects | HCT | immunosuppressive treatment 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 CMVspecific 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 (≥0.5mg/kg) and high-dose (≥1mg/kg) corticosteroids, especially within 2–4 weeks before testing, significantly suppressed Tcell responses, though rapid tapering preserved function. Prolonged administration of MMF (≥2000mg) 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. 1 | Introduction Cytomegalovirus (CMV) specific T-cell responses play an important role in controlling CMV infection in allogeneichematopoietic cell transplant (HCT) recipients, and current clinical strategies increasingly incorporate cell-mediated immunity into monitoring protocols [1–4] . In addition to interferon gamma (IFN-γ), polyfunctional T-cells produce other cytokines and may offer stronger antiviral protection [5, 6] . As CMV complications continue to occur [7–10], a deeper understanding of the factors influencing CMV-specific T-cell polyfunctionality is critical for managing refractory or resistant CMV infections and for guiding the design of T-cell therapy trials, especially as modern transplant approaches increase the risk of viral complications [9] . Transplant recipients face severe immune modulation from a range of treatments and prophylaxis, affecting cell-mediated immunity and protection from novel and latent infections ina myriad of ways. Corticosteroids are a known suppressor of T-cell immunity, but existing data are based on outdated assays and do not account for other commonly used immunosuppressants [11] . Although clinical practice now favorslower corticosteroid doses [12, 13], the effects of these moderate exposures on CMV-specific immunity remain poorly characterized. Similarly, the impact of other agents such as This is an open access article under the terms of the Creative Commons Attribution License, which permits use, dis

FAQs

Which immunosuppressive agents and timing factors are evaluated for their effects on CMV-specific T-cell polyfunctionality?

The study compares timing and dosing effects of PT-Cy, corticosteroids, MMF, and CNIs, with T-cell responses evaluated after pp65 stimulation within 100 days post-HCT.

What is the overall frequency of polyfunctional CMV-specific CD4+ and CD8+ responses among the studied patients?

Among 243 patients, 31% exhibited polyfunctional CD4+ and CD8+ responses.

How do corticosteroids and MMF influence CMV-specific T-cell polyfunctionality?

Intermediate and high-dose corticosteroids significantly suppress T-cell responses, especially when given within 2–4 weeks before testing, while rapid tapering preserves function. Prolonged MMF administration (≥2000 mg) diminishes CMV-specific T-cell polyfunctionality.

Sep 29, 2026

Uploaded by Aurelia