Homeostatic proliferation as an isolated variable reverses CD8+ T cell anergy and promotes tumor rejection
Abstract
Although recent work has suggested that lymphopenia-induced homeostatic proliferation may improve T cell-mediated tumor rejection, there is little direct evidence isolating homeostatic proliferation as an experimental variable, and the mechanism by which improved antitumor immunity occurs via homeostatic proliferation is poorly understood. An adoptive transfer model was developed in which tumor-specific 2C/RAG2−/− TCR transgenic CD8+ T cells were introduced either into the lymphopenic environment of RAG2−/− mice or into P14/RAG2−/− mice containing an irrelevant CD8+ TCR transgenic population. RAG2−/−, but not P14/RAG2−/− recipients supported homeostatic proliferation of transferred T cells as well as tumor rejection. Despite absence of tumor rejection in P14/RAG2−/− recipients, 2C cells did become activated, as reflected by CFSE dilution and CD44 up-regulation. However, these cells showed poor IFN-γ and IL-2 production upon restimulation, consistent with T cell anergy and similar to the hyporesponsiveness induced by administration of soluble peptide Ag. To determine whether homeostatic proliferation could uncouple T cell anergy, anergic 2C cells were transferred into RAG−/− recipients, which resulted in vigorous homeostatic proliferation, recovery of IL-2 production, and acquisition of the ability to reject tumors. Taken together, our data suggest that a major mechanism by which homeostatic proliferation supports tumor rejection is by maintaining and/or re-establishing T cell responsiveness.
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In a lymphopenic host, homeostatic proliferation of anti-tumor T cells reverses anergy and promotes tumor rejection in vivo.
“Homeostatic proliferation of anti-tumor T cells in a lymphopenic host both reverses anergy and promotes tumor rejection in vivo [14].”
From T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment (2013) · cites this paper as [14]
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- Authors
- Brown, I. E., Blank, C., Kline, J., Kacha, A. K., & Gajewski, T. F.
- Affiliations
- University of Chicago (US)
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2006-10-01
- Volume
- 177
- Issue
- 7
- Pages
- 4521-4529
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W1915573821
- Cited by
- 91
- References
- 62
- Citations by year
- 2025: 2 · 2024: 2 · 2023: 1 · 2022: 1 · 2020: 2 · 2019: 1 · 2018: 2 · 2017: 6 · 2016: 6 · 2015: 3 · 2014: 4 · 2013: 12 · 2012: 11
- FWCI
- 2.77
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (P01CA97296, P01CA097296)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- homeostatic proliferation, CD8+ T cells, T cell anergy, tumor rejection, lymphopenia, adoptive T cell therapy, TCR transgenic T cells, Rag2 knockout mice, T cell hyporesponsiveness, IL-2 production, interferon-gamma, antitumor immunity
- MeSH terms
- Animals, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Homeostasis, Lymphopenia, Mice, Transgenic, Neoplasms, Experimental, Receptors, Antigen, T-Cell, Cytokines, Genes, RAG-1, Clonal Anergy, CD8-Positive T-Lymphocytes, Adoptive Transfer, Cell Proliferation, Mice
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