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.
| Original language | English |
|---|---|
| Article number | 5631 |
| Journal | Nature Communications |
| Volume | 14 |
| Issue number | 1 |
| DOIs | |
| State | Published - Dec 2023 |
Bibliographical note
Publisher Copyright:© 2023, Springer Nature Limited.
Funding
The authors would like to thank all the current and former members in the Tinoco Laboratory for all their constructive comments and advice during this project. We would like to thank Dr. Jennifer Atwood at the UCI Institute for Immunology Flow Core, a shared resource of the Cancer Center Support Grant (CA-62203) at the University of California, Irvine, for assistance with imaging flow cytometry and FACS. We would like to thank Dr. Jie Wu and Dr. Melanie Oakes at the UCI Genomics High Throughput Facility (UCI GHTF) for setup and analysis of RNA-sequencing and setup of ATAC-sequencing data, which is a Chao Family Comprehensive Cancer Center (CFCCC) shared resource supported by the Cancer Center Support Grant (P30CA062203). The UCI GHTF is another shared resource of the Cancer Center Support Grant (CA-62203) at the University of California, Irvine, and NIH shared instrumentation grants 1S10RR025496-01, 1S10OD010794-01, and 1S10OD021718-01. We would like to thank Makena Ewald for technical assistance on naïve T cell characterization experiments. We would like to thank Drs. Mohamed Abdel-Hakeem and E. John Wherry for sharing their data of “scarred” gene list signatures. Figures 2 a, 2 e, 3 a, 3 e, 6 a, and 6f were created with BioRender.com (https://biorender.com ). This work was supported by the National Institutes of Health (R01 AI137239 to R.T. and R37 CA252081 to R.B.) Department of Defense (W81XWH-18-1-0738 to R.T.), The Melanoma Research Alliance (571135 to R.T.), The American Cancer Society (Institutional Research Grant IRG-16-187-13 to R.T.), T32 virus-host interactions: a multi-scale training program (T32AI007319 to E.N.N.), T32 training grant in Cancer Biology and Therapeutics (T32CA009054 to J.M.D.), T32 Microbiology and Infectious Diseases training grant (T32AI141346 to K.M.V.), NIH IMDS training grant (GM055246 to K.M.V.), and an EMBO postdoctoral fellowship (ALTF 213-2022 to P.O.). The authors would like to thank all the current and former members in the Tinoco Laboratory for all their constructive comments and advice during this project. We would like to thank Dr. Jennifer Atwood at the UCI Institute for Immunology Flow Core, a shared resource of the Cancer Center Support Grant (CA-62203) at the University of California, Irvine, for assistance with imaging flow cytometry and FACS. We would like to thank Dr. Jie Wu and Dr. Melanie Oakes at the UCI Genomics High Throughput Facility (UCI GHTF) for setup and analysis of RNA-sequencing and setup of ATAC-sequencing data, which is a Chao Family Comprehensive Cancer Center (CFCCC) shared resource supported by the Cancer Center Support Grant (P30CA062203). The UCI GHTF is another shared resource of the Cancer Center Support Grant (CA-62203) at the University of California, Irvine, and NIH shared instrumentation grants 1S10RR025496-01, 1S10OD010794-01, and 1S10OD021718-01. We would like to thank Makena Ewald for technical assistance on naïve T cell characterization experiments. We would like to thank Drs. Mohamed Abdel-Hakeem and E. John Wherry for sharing their data of “scarred” gene list signatures. Figures a, e, a, e, a, and were created with BioRender.com ( https://biorender.com ). This work was supported by the National Institutes of Health (R01 AI137239 to R.T. and R37 CA252081 to R.B.) Department of Defense (W81XWH-18-1-0738 to R.T.), The Melanoma Research Alliance (571135 to R.T.), The American Cancer Society (Institutional Research Grant IRG-16-187-13 to R.T.), T32 virus-host interactions: a multi-scale training program (T32AI007319 to E.N.N.), T32 training grant in Cancer Biology and Therapeutics (T32CA009054 to J.M.D.), T32 Microbiology and Infectious Diseases training grant (T32AI141346 to K.M.V.), NIH IMDS training grant (GM055246 to K.M.V.), and an EMBO postdoctoral fellowship (ALTF 213-2022 to P.O.).
| Funders | Funder number |
|---|---|
| Tinoco Laboratory | |
| Chao Family Comprehensive Cancer Center | |
| University of California Irvine | |
| Melanoma Research Alliance Foundation | 571135 |
| Markey Cancer Center's Cancer Center Support | CA-62203, P30CA062203 |
| National Institutes of Health (NIH) | 1S10OD021718-01, GM055246, R37 CA252081, R01 AI137239, 1S10OD010794-01, 1S10RR025496-01 |
| European Molecular Biology Organization | ALTF 213-2022 |
| American Cancer Society-Michigan Cancer Research Fund | T32CA009054, GM055246, T32AI007319, T32AI141346, IRG-16-187-13 |
| U.S. Department of Defense | W81XWH-18-1-0738 |
UN SDGs
This output contributes to the following UN Sustainable Development Goals (SDGs)
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SDG 3 Good Health and Well-being
ASJC Scopus subject areas
- General Chemistry
- General Biochemistry, Genetics and Molecular Biology
- General
- General Physics and Astronomy
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