IRF4 impedes human CD8 T cell function and promotes cell proliferation and PD-1 expression
Thibault Hirsch,
Damien Neyens,
Céline Duhamel,
Alexandre Bayard,
Christophe Vanhaver,
Mathieu Luyckx,
Francisco Sala de Oyanguren,
Claude Wildmann,
Nicolas Dauguet,
Jean-Luc Squifflet,
Virginie Montiel,
Mélanie Deschamps,
Pierre van der Bruggen
Affiliations
Thibault Hirsch
De Duve Institute, Université Catholique de Louvain, Brussels, Belgium; Corresponding author
Damien Neyens
De Duve Institute, Université Catholique de Louvain, Brussels, Belgium
Céline Duhamel
De Duve Institute, Université Catholique de Louvain, Brussels, Belgium
Alexandre Bayard
De Duve Institute, Université Catholique de Louvain, Brussels, Belgium
Christophe Vanhaver
De Duve Institute, Université Catholique de Louvain, Brussels, Belgium
Mathieu Luyckx
De Duve Institute, Université Catholique de Louvain, Brussels, Belgium; Département de Gynécologie, Cliniques Universitaires Saint-Luc, Brussels, Belgium
Francisco Sala de Oyanguren
Flow Cytometry Facility, University of Lausanne, Lausanne, Switzerland
Claude Wildmann
De Duve Institute, Université Catholique de Louvain, Brussels, Belgium
Nicolas Dauguet
De Duve Institute, Université Catholique de Louvain, Brussels, Belgium
Jean-Luc Squifflet
Département de Gynécologie, Cliniques Universitaires Saint-Luc, Brussels, Belgium
Virginie Montiel
Unité de Soins Intensifs, Cliniques Universitaires Saint-Luc, Brussels, Belgium
Mélanie Deschamps
Unité de Soins Intensifs, Cliniques Universitaires Saint-Luc, Brussels, Belgium
Pierre van der Bruggen
De Duve Institute, Université Catholique de Louvain, Brussels, Belgium; WELBIO Department, WEL Research Institute, Wavre, Belgium
Summary: Human CD8 tumor-infiltrating lymphocytes (TILs) with impaired effector functions and PD-1 expression are categorized as exhausted. However, the exhaustion-like features reported in TILs might stem from their activation rather than the consequence of T cell exhaustion itself. Using CRISPR-Cas9 and lentiviral overexpression in CD8 T cells from non-cancerous donors, we show that the T cell receptor (TCR)-induced transcription factor interferon regulatory factor 4 (IRF4) promotes cell proliferation and PD-1 expression and hampers effector functions and expression of nuclear factor κB (NF-κB)-regulated genes. While CD8 TILs with impaired interferon γ (IFNγ) production exhibit activation markers IRF4 and CD137 and exhaustion markers thymocyte selection associated high mobility group box (TOX) and PD-1, activated T cells in patients with COVID-19 do not demonstrate elevated levels of TOX and PD-1. These results confirm that IRF4+ TILs are exhausted rather than solely activated. Our study indicates, however, that PD-1 expression, low IFNγ production, and active cycling in TILs are all influenced by IRF4 upregulation after T cell activation.
