# NFAT single-deficient murine T cells reduce the risk of aGvHD while controlling cytomegalovirus infection

## TL;DR

NFAT-deficient T cells reduce graft-versus-host disease without compromising the ability to fight cytomegalovirus infections.

## Contribution

NFAT-deficient T cells ameliorate GvHD while maintaining anti-CMV immunity in mice.

## Key findings

- NFAT-deficient T cells show reduced proinflammatory and cytotoxic potential.
- NFAT-deficient CD8+ T cells expand more and produce higher IFN-γ and GzmB to control CMV.
- NFAT-deficient T cells can migrate to non-lymphoid tissues to combat CMV.

## 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.

•NFAT-deficient co-transplanted T cells ameliorate GvHD despite MCMV infection•NFAT-deficient T cells express less pro-inflammatory and cytotoxic molecules•NFAT-deficient MCMV-responsive CD8+ T cells expand with heightened IFN-γ and GzmB•NFAT-deficient T cells control MCMV better than WT T cells

NFAT-deficient co-transplanted T cells ameliorate GvHD despite MCMV infection

NFAT-deficient T cells express less pro-inflammatory and cytotoxic molecules

NFAT-deficient MCMV-responsive CD8+ T cells expand with heightened IFN-γ and GzmB

NFAT-deficient T cells control MCMV better than WT T cells

Immunology; Virology