IRF4 impedes human CD8 T cell function and promotes cell proliferation and PD-1 expression.

Area of Science:

• Immunology
• Cancer Biology
• T cell biology

Background:

• Human CD8 tumor-infiltrating lymphocytes (TILs) exhibiting impaired effector functions and PD-1 expression are often classified as exhausted.
• However, these exhaustion-like features in TILs could potentially arise from T cell activation rather than true T cell exhaustion.

Purpose of the Study:

• To investigate the role of the transcription factor interferon regulatory factor 4 (IRF4) in CD8 TIL exhaustion.
• To differentiate between activation-induced phenotypes and genuine exhaustion in TILs.

Main Methods:

• Utilized CRISPR-Cas9 and lentiviral overexpression in CD8 T cells from non-cancerous donors.
• Analyzed transcription factor activity, cell proliferation, PD-1 expression, effector functions, and gene expression related to nuclear factor κB (NF-κB).
• Compared TILs with activated T cells from COVID-19 patients.

Main Results:

• TCR-induced IRF4 promotes CD8 T cell proliferation and PD-1 expression while hindering effector functions and NF-κB-regulated gene expression.
• CD8 TILs with reduced interferon γ (IFNγ) production show activation markers (IRF4, CD137) and exhaustion markers (TOX, PD-1).
• Activated T cells in COVID-19 patients do not exhibit elevated TOX and PD-1 levels, distinguishing them from exhausted TILs.

Conclusions:

• IRF4 upregulation in TILs leads to exhaustion, characterized by PD-1 expression, reduced IFNγ production, and active cycling.
• The findings confirm that IRF4+ TILs are indeed exhausted, not merely activated.
• IRF4 plays a crucial role in modulating PD-1 expression, IFNγ production, and cell cycling in TILs post-activation.