The Ubiquitin Ligase Adaptor NDFIP1 Selectively Enforces a CD8+ T Cell Tolerance Checkpoint to High-Dose Antigen
Summary: Escape from peripheral tolerance checkpoints that control cytotoxic CD8+ T cells is important for cancer immunotherapy and autoimmunity, but pathways enforcing these checkpoints are mostly uncharted. We reveal that the HECT-type ubiquitin ligase activator, NDFIP1, enforces a cell-intrinsic...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2018-07-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124718309872 |
| _version_ | 1818143070658494464 |
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| author | Mayura V. Wagle Julia M. Marchingo Jason Howitt Seong-Seng Tan Christopher C. Goodnow Ian A. Parish |
| author_facet | Mayura V. Wagle Julia M. Marchingo Jason Howitt Seong-Seng Tan Christopher C. Goodnow Ian A. Parish |
| author_sort | Mayura V. Wagle |
| collection | DOAJ |
| description | Summary: Escape from peripheral tolerance checkpoints that control cytotoxic CD8+ T cells is important for cancer immunotherapy and autoimmunity, but pathways enforcing these checkpoints are mostly uncharted. We reveal that the HECT-type ubiquitin ligase activator, NDFIP1, enforces a cell-intrinsic CD8+ T cell checkpoint that desensitizes TCR signaling during in vivo exposure to high antigen levels. Ndfip1-deficient OT-I CD8+ T cells responding to high exogenous tolerogenic antigen doses that normally induce anergy aberrantly expanded and differentiated into effector cells that could precipitate autoimmune diabetes in RIP-OVAhi mice. In contrast, NDFIP1 was dispensable for peripheral deletion to low-dose exogenous or pancreatic islet-derived antigen and had little impact upon effector responses to Listeria or acute LCMV infection. These data provide evidence that NDFIP1 mediates a CD8+ T cell tolerance checkpoint, with a different mechanism to CD4+ T cells, and indicates that CD8+ T cell deletion and anergy are molecularly separable checkpoints. : Ndfip1 restrains CD4+ T cell differentiation, but its role in CD8+ T cells is unclear. Wagle et al. show that Ndfip1 selectively enforces peripheral CD8+ T cell tolerance to abundant antigen while minimally affecting both CD8+ T cell tolerance to scarce antigen and effector expansion and differentiation during acute infection. Keywords: T cell, checkpoint, peripheral tolerance, autoimmunity, anergy, ubiquitin ligases, Ndfip1 |
| first_indexed | 2024-12-11T11:25:50Z |
| format | Article |
| id | doaj.art-f1df04bb8c3940ffbd9e365a5f64deff |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-11T11:25:50Z |
| publishDate | 2018-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-f1df04bb8c3940ffbd9e365a5f64deff2022-12-22T01:09:00ZengElsevierCell Reports2211-12472018-07-01243577584The Ubiquitin Ligase Adaptor NDFIP1 Selectively Enforces a CD8+ T Cell Tolerance Checkpoint to High-Dose AntigenMayura V. Wagle0Julia M. Marchingo1Jason Howitt2Seong-Seng Tan3Christopher C. Goodnow4Ian A. Parish5John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia; Garvan Institute of Medical Research, Sydney, NSW, AustraliaDivision of Immunology, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC, AustraliaThe Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia; Department of Health and Medical Sciences, Swinburne University, Melbourne, VIC, AustraliaThe Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, AustraliaJohn Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia; Garvan Institute of Medical Research, Sydney, NSW, Australia; St Vincent’s Clinical School, University of New South Wales, Sydney, NSW, Australia; Corresponding authorJohn Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia; Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Corresponding authorSummary: Escape from peripheral tolerance checkpoints that control cytotoxic CD8+ T cells is important for cancer immunotherapy and autoimmunity, but pathways enforcing these checkpoints are mostly uncharted. We reveal that the HECT-type ubiquitin ligase activator, NDFIP1, enforces a cell-intrinsic CD8+ T cell checkpoint that desensitizes TCR signaling during in vivo exposure to high antigen levels. Ndfip1-deficient OT-I CD8+ T cells responding to high exogenous tolerogenic antigen doses that normally induce anergy aberrantly expanded and differentiated into effector cells that could precipitate autoimmune diabetes in RIP-OVAhi mice. In contrast, NDFIP1 was dispensable for peripheral deletion to low-dose exogenous or pancreatic islet-derived antigen and had little impact upon effector responses to Listeria or acute LCMV infection. These data provide evidence that NDFIP1 mediates a CD8+ T cell tolerance checkpoint, with a different mechanism to CD4+ T cells, and indicates that CD8+ T cell deletion and anergy are molecularly separable checkpoints. : Ndfip1 restrains CD4+ T cell differentiation, but its role in CD8+ T cells is unclear. Wagle et al. show that Ndfip1 selectively enforces peripheral CD8+ T cell tolerance to abundant antigen while minimally affecting both CD8+ T cell tolerance to scarce antigen and effector expansion and differentiation during acute infection. Keywords: T cell, checkpoint, peripheral tolerance, autoimmunity, anergy, ubiquitin ligases, Ndfip1http://www.sciencedirect.com/science/article/pii/S2211124718309872 |
| spellingShingle | Mayura V. Wagle Julia M. Marchingo Jason Howitt Seong-Seng Tan Christopher C. Goodnow Ian A. Parish The Ubiquitin Ligase Adaptor NDFIP1 Selectively Enforces a CD8+ T Cell Tolerance Checkpoint to High-Dose Antigen Cell Reports |
| title | The Ubiquitin Ligase Adaptor NDFIP1 Selectively Enforces a CD8+ T Cell Tolerance Checkpoint to High-Dose Antigen |
| title_full | The Ubiquitin Ligase Adaptor NDFIP1 Selectively Enforces a CD8+ T Cell Tolerance Checkpoint to High-Dose Antigen |
| title_fullStr | The Ubiquitin Ligase Adaptor NDFIP1 Selectively Enforces a CD8+ T Cell Tolerance Checkpoint to High-Dose Antigen |
| title_full_unstemmed | The Ubiquitin Ligase Adaptor NDFIP1 Selectively Enforces a CD8+ T Cell Tolerance Checkpoint to High-Dose Antigen |
| title_short | The Ubiquitin Ligase Adaptor NDFIP1 Selectively Enforces a CD8+ T Cell Tolerance Checkpoint to High-Dose Antigen |
| title_sort | ubiquitin ligase adaptor ndfip1 selectively enforces a cd8 t cell tolerance checkpoint to high dose antigen |
| url | http://www.sciencedirect.com/science/article/pii/S2211124718309872 |
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