Robust Iterative Stimulation with Self-Antigens Overcomes CD8+ T Cell Tolerance to Self- and Tumor Antigens
Summary: The immune system adapts to constitutive antigens to preserve self-tolerance, which is a major barrier for anti-tumor immunity. Antigen-specific reversal of tolerance constitutes a major goal to spur therapeutic applications. Here, we show that robust, iterative, systemic stimulation target...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2019-09-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124719310782 |
| _version_ | 1818293548565397504 |
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| author | Christine E. Nelson Emily A. Thompson Clare F. Quarnstrom Kathryn A. Fraser Davis M. Seelig Siddheshvar Bhela Brandon J. Burbach David Masopust Vaiva Vezys |
| author_facet | Christine E. Nelson Emily A. Thompson Clare F. Quarnstrom Kathryn A. Fraser Davis M. Seelig Siddheshvar Bhela Brandon J. Burbach David Masopust Vaiva Vezys |
| author_sort | Christine E. Nelson |
| collection | DOAJ |
| description | Summary: The immune system adapts to constitutive antigens to preserve self-tolerance, which is a major barrier for anti-tumor immunity. Antigen-specific reversal of tolerance constitutes a major goal to spur therapeutic applications. Here, we show that robust, iterative, systemic stimulation targeting tissue-specific antigens in the context of acute infections reverses established CD8+ T cell tolerance to self, including in T cells that survive negative selection. This strategy results in large numbers of circulating and resident memory self-specific CD8+ T cells that are widely distributed and can be co-opted to control established malignancies bearing self-antigen without concomitant autoimmunity. Targeted expansion of both self- and tumor neoantigen-specific T cells acts synergistically to boost anti-tumor immunity and elicits protection against aggressive melanoma. Our findings demonstrate that T cell tolerance can be re-adapted to responsiveness through robust antigenic exposure, generating self-specific CD8+ T cells that can be used for cancer treatment. : Nelson et al. show that immune tolerance to self is not a fixed state and can be overcome with robust, iterative stimulation in the context of infection. Autoreactive CD8+ T cells expanded with this method can be co-opted to target tumors bearing shared self-antigen without associated autoimmunity. Keywords: CD8 T cell, tolerance, reversal, exhaustion, dysfunction, cancer, self-antigen, neo-antigen, resident memory, vaccination |
| first_indexed | 2024-12-13T03:17:36Z |
| format | Article |
| id | doaj.art-f2ed85c1525a4117a9fddec93eec624d |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-13T03:17:36Z |
| publishDate | 2019-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-f2ed85c1525a4117a9fddec93eec624d2022-12-22T00:01:25ZengElsevierCell Reports2211-12472019-09-01281230923104.e5Robust Iterative Stimulation with Self-Antigens Overcomes CD8+ T Cell Tolerance to Self- and Tumor AntigensChristine E. Nelson0Emily A. Thompson1Clare F. Quarnstrom2Kathryn A. Fraser3Davis M. Seelig4Siddheshvar Bhela5Brandon J. Burbach6David Masopust7Vaiva Vezys8Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA; Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55455, USACenter for Immunology, University of Minnesota, Minneapolis, MN 55455, USA; Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55455, USACenter for Immunology, University of Minnesota, Minneapolis, MN 55455, USA; Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55455, USACenter for Immunology, University of Minnesota, Minneapolis, MN 55455, USA; Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55455, USADepartment of Veterinary Clinical Sciences, University of Minnesota, St. Paul, MN 55118, USACenter for Immunology, University of Minnesota, Minneapolis, MN 55455, USA; Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55455, USACenter for Immunology, University of Minnesota, Minneapolis, MN 55455, USA; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USACenter for Immunology, University of Minnesota, Minneapolis, MN 55455, USA; Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55455, USACenter for Immunology, University of Minnesota, Minneapolis, MN 55455, USA; Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55455, USA; Corresponding authorSummary: The immune system adapts to constitutive antigens to preserve self-tolerance, which is a major barrier for anti-tumor immunity. Antigen-specific reversal of tolerance constitutes a major goal to spur therapeutic applications. Here, we show that robust, iterative, systemic stimulation targeting tissue-specific antigens in the context of acute infections reverses established CD8+ T cell tolerance to self, including in T cells that survive negative selection. This strategy results in large numbers of circulating and resident memory self-specific CD8+ T cells that are widely distributed and can be co-opted to control established malignancies bearing self-antigen without concomitant autoimmunity. Targeted expansion of both self- and tumor neoantigen-specific T cells acts synergistically to boost anti-tumor immunity and elicits protection against aggressive melanoma. Our findings demonstrate that T cell tolerance can be re-adapted to responsiveness through robust antigenic exposure, generating self-specific CD8+ T cells that can be used for cancer treatment. : Nelson et al. show that immune tolerance to self is not a fixed state and can be overcome with robust, iterative stimulation in the context of infection. Autoreactive CD8+ T cells expanded with this method can be co-opted to target tumors bearing shared self-antigen without associated autoimmunity. Keywords: CD8 T cell, tolerance, reversal, exhaustion, dysfunction, cancer, self-antigen, neo-antigen, resident memory, vaccinationhttp://www.sciencedirect.com/science/article/pii/S2211124719310782 |
| spellingShingle | Christine E. Nelson Emily A. Thompson Clare F. Quarnstrom Kathryn A. Fraser Davis M. Seelig Siddheshvar Bhela Brandon J. Burbach David Masopust Vaiva Vezys Robust Iterative Stimulation with Self-Antigens Overcomes CD8+ T Cell Tolerance to Self- and Tumor Antigens Cell Reports |
| title | Robust Iterative Stimulation with Self-Antigens Overcomes CD8+ T Cell Tolerance to Self- and Tumor Antigens |
| title_full | Robust Iterative Stimulation with Self-Antigens Overcomes CD8+ T Cell Tolerance to Self- and Tumor Antigens |
| title_fullStr | Robust Iterative Stimulation with Self-Antigens Overcomes CD8+ T Cell Tolerance to Self- and Tumor Antigens |
| title_full_unstemmed | Robust Iterative Stimulation with Self-Antigens Overcomes CD8+ T Cell Tolerance to Self- and Tumor Antigens |
| title_short | Robust Iterative Stimulation with Self-Antigens Overcomes CD8+ T Cell Tolerance to Self- and Tumor Antigens |
| title_sort | robust iterative stimulation with self antigens overcomes cd8 t cell tolerance to self and tumor antigens |
| url | http://www.sciencedirect.com/science/article/pii/S2211124719310782 |
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