# IRF4 Mediates Immune Evasion to Facilitate EBV Transformation

## TL;DR

This study shows that IRF4 helps EBV-infected cells evade the immune system by increasing PD1/PD-L1, and functional CD4+ T cells are crucial for controlling EBV infection.

## Contribution

The study reveals IRF4's role in immune evasion during EBV transformation by regulating PD1/PD-L1 expression.

## Key findings

- IRF4 transcriptionally regulates PD1 and PD-L1 to suppress T cell functions during EBV infection.
- Depleting IRF4 in EBV+ cells reduces PD1/PD-L1 and partially restores CD4+ T cell activity.
- CD4+ T cell depletion increases EBV transformation efficiency, especially in HIV patients.

## Abstract

The lymphocyte-specific transcription factor interferon regulatory factor 4 (IRF4) is a key player in immune evasion in cancers, with the complex mechanism(s) being barely understood. In this study, we have focused on the role of IRF4 in regulating T cell functions through its transcriptional regulation of programmed death 1 (PD1) and its ligand PD1 ligand 1 (PD-L1), which were identified as IRF4 transcriptional targets in multi-omics analysis. We have shown that IRF4 transcriptionally regulates both PD1 and PD-L1, promoting immune suppression in the context of Epstein–Barr virus (EBV) infection. Co-culturing EBV+ JiJoye lymphoma cells with CD4+ T cells or with peripheral blood mononuclear cells (PBMCs) downregulates CD4+ T cell functions, but the depletion of IRF4 in EBV+ JiJoye lymphoma cells reduces PD1 and PD-L1 expression, and partially restores CD4+ T cell functions. Moreover, CD4+ T cell depletion from PBMCs enhances EBV transformation, and EBV has a greater efficiency in transforming PBMCs from HIV patients with impaired CD4+ T cell functions. These findings support the role of IRF4 in immune evasion by upregulating PD1/PD-L1 during EBV transformation, and that functional CD4+ T cells are essential for limiting EBV transformation.