HMGB2 regulates the differentiation and stemness of exhausted CD8+ T cells during chronic viral infection and cancer
Year: 2023
Type: article
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.
Source: Nature Communications
Language: English
Topic: T-cell and B-cell Immunology
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,290
Funders: U.S. Department of Defense, Foundation for the National Institutes of Health, U.S. Department of Health and Human Services, Melanoma Research Alliance, National Institutes of Health, University of California, Irvine, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Center for Research Resources, Office of Extramural Research, National Institutes of Health, Chao Family Comprehensive Cancer Center
Awards: G1315042094, Molecular Mechanisms of APOBEC-Induced Mutagenesis in Cancer, G1738746289, PSGL-1 mechanisms of T cell exhaustion, G2670393129, High-Throughput DNA Sequencer, G2947711961, G2980620740, G4119534169, G4631142862, G5025827294, G5033441356, High Throughput DNA Sequencer, G5849328965, G5850682332, G5980120469, TARGETING THE PSGL-1 IMMUNE CHECKPOINT TO PROMOTE MELANOMA TUMOR CONTROL, G6051724979, G6152400718, G7287687763, Targeting PSGL-1 inhibitory pathways to promote anti-tumor T cell immunity, G8166743225, PacBio RS Single Molecule, Real-Time (SMRT) DNA Sequencer, MBRS IMSD Program at the University of California, Irvine, G9000088035, G9000120903, G9000323020, Cancer Center Support Grant, A Training Program for Interdisciplinary Cancer Research, T32 for Training in Microbiology & Infectious Diseases, G926171932
OpenAlex ID: W4386723137