HMGB2 regulates the differentiation and stemness of exhausted CD8+ T cells during chronic viral infection and cancer

Emily N. Neubert, Julia M. DeRogatis, Sloan A. Lewis, Karla M. Viramontes, Pedro Ortega, Monique L. Henriquez, Rémi Buisson, Ilhem Messaoudi and Roberto Tinoco ()
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Emily N. Neubert: University of California Irvine
Julia M. DeRogatis: University of California Irvine
Sloan A. Lewis: University of California Irvine
Karla M. Viramontes: University of California Irvine
Pedro Ortega: University of California, Irvine
Monique L. Henriquez: University of California Irvine
Rémi Buisson: University of California Irvine
Ilhem Messaoudi: University of Kentucky
Roberto Tinoco: University of California Irvine

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-41352-0

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