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Updated: May 24, 2025
Generation of Multivirus-specific T Cells to Prevent/treat Viral Infections after Allogeneic Hematopoietic Stem Cell Transplant
Published on: May 27, 2011
NFAT single-deficient murine T cells reduce the risk of aGvHD while controlling cytomegalovirus infection
Nadine Hundhausen1, Snigdha Majumder1, Yin Xiao1
1Institute of Pathology, Julius-Maximilians-University Würzburg, Würzburg, Germany.
Abstract:
NFAT is a family of transcription factors whose activation is inhibited by calcineurin inhibitors (CNIs). In allogeneic hematopoietic stem cell transplantation (allo-HCT), CNIs are employed to prevent and treat graft-versus-host disease (GvHD). Unfortunately, control of cytomegalovirus (CMV), which exacerbates clinical outcomes, is simultaneously lost. Since single NFAT deficiency in T cells ameliorates GvHD in our major mismatch model, we investigated whether protection is maintained during CMV infection. Reassuringly, NFAT-deficient T cells still improved GvHD upon acute CMV infection and after allo-HCT in latently CMV-infected mice, showing reduced proinflammatory and cytotoxic potential. In sharp contrast, CMV-specific NFAT-deficient CD8+ inflated memory T cells expanded more and with higher levels of interferon gamma (IFN-γ) and GzmB expression, effectively controlling CMV. Notably, NFAT-deficient inflated memory T cells could migrate to non-lymphoid tissues and fight CMV. Therefore, CMV infection does not interfere with the protective effect of NFAT inhibition to attenuate GvHD while allowing an anti-CMV response.
Insights
In allogeneic stem cell transplants, inhibiting NFAT reduces graft-versus-host disease (GvHD) without compromising cytomegalovirus (CMV) control. NFAT-deficient T cells effectively manage CMV while mitigating GvHD.
Area of Science:
- Immunology
- Transplantation immunology
- Virology
Background:
- Calcineurin inhibitors (CNIs) manage graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (allo-HCT).
- CNI use impairs cytomegalovirus (CMV) control, worsening patient outcomes.
- NFAT deficiency in T cells ameliorates GvHD in major mismatch models.
Purpose of the Study:
- To investigate if NFAT deficiency protects against GvHD during CMV infection post-allo-HCT.
- To assess the impact of NFAT deficiency on anti-CMV immune responses.
Main Methods:
- Utilized a major mismatch allo-HCT model in mice.
- Induced acute and latent CMV infections.
- Analyzed T cell responses, including GvHD severity, inflammation, cytotoxicity, and CMV-specific memory T cell expansion and function.
Main Results:
- NFAT-deficient T cells reduced GvHD severity during acute and latent CMV infection post-allo-HCT.
- CMV-specific NFAT-deficient CD8+ memory T cells exhibited enhanced expansion and effector function (IFN-γ, GzmB).
- These NFAT-deficient T cells effectively controlled CMV and migrated to non-lymphoid tissues.
Conclusions:
- NFAT inhibition attenuates GvHD post-allo-HCT, even during CMV infection.
- NFAT deficiency permits robust anti-CMV T cell responses, including enhanced memory cell function and tissue migration.
- This dual protection suggests NFAT inhibition is a viable strategy in CMV-positive allo-HCT recipients.
