HMGB2 regulates the differentiation and stemness of exhausted CD8+ T cells during chronic viral infection and cancer
Abstract
Chronic infections and cancers evade the host immune system through mechanisms that induce T cell exhaustion. The heterogeneity within the exhausted CD8+ T cell pool has revealed the importance of stem-like progenitor (Tpex) and terminal (Tex) exhausted T cells, although the mechanisms underlying their development are not fully known. Here we report High Mobility Group Box 2 (HMGB2) protein expression is upregulated and sustained in exhausted CD8+ T cells, and HMGB2 expression is critical for their differentiation. Through epigenetic and transcriptional programming, we identify HMGB2 as a cell-intrinsic regulator of the differentiation and maintenance of Tpex cells during chronic viral infection and in tumors. Despite Hmgb2−/− CD8+ T cells expressing TCF-1 and TOX, these master regulators were unable to sustain Tpex differentiation and long-term survival during persistent antigen. Furthermore, HMGB2 also had a cell-intrinsic function in the differentiation and function of memory CD8+ T cells after acute viral infection. Our findings show that HMGB2 is a key regulator of CD8+ T cells and may be an important molecular target for future T cell-based immunotherapies.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Sep 13, 2023
- Source ID
- 10.1038/s41467-023-41352-0
Entities
People
- Emily N. Neubert
- Ilhem Messaoudi
- Julia M. Derogatis
- Karla M. Viramontes
- Monique L Henriquez
- Pedro Ortega
- Roberto Tinoco
- Rémi Buisson
- Sloan A. Lewis
Organizations
- Foundation for the National Institutes of Health
- Melanoma Research Alliance
- Office of Extramural Research
- United States Department of Defense