SLAM/SAP signaling regulates discrete γδ T cell developmental checkpoints and shapes the innate-like γδ TCR repertoire
During thymic development, most γδ T cells acquire innate-like characteristics that are critical for their function in tumor surveillance, infectious disease, and tissue repair. The mechanisms, however, that regulate γδ T cell developmental programming remain unclear. Recently, we demonstrated that...
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eLife Sciences Publications Ltd
2024-12-01
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| Online Access: | https://elifesciences.org/articles/97229 |
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| author | Somen K Mistri Brianna M Hilton Katherine J Horrigan Emma S Andretta Remi Savard Oliver Dienz Kenneth J Hampel Diana L Gerrard Joshua T Rose Nikoletta Sidiropoulos Dev Majumdar Jonathan E Boyson |
| author_facet | Somen K Mistri Brianna M Hilton Katherine J Horrigan Emma S Andretta Remi Savard Oliver Dienz Kenneth J Hampel Diana L Gerrard Joshua T Rose Nikoletta Sidiropoulos Dev Majumdar Jonathan E Boyson |
| author_sort | Somen K Mistri |
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| description | During thymic development, most γδ T cells acquire innate-like characteristics that are critical for their function in tumor surveillance, infectious disease, and tissue repair. The mechanisms, however, that regulate γδ T cell developmental programming remain unclear. Recently, we demonstrated that the SLAM/SAP signaling pathway regulates the development and function of multiple innate-like γδ T cell subsets. Here, we used a single-cell proteogenomics approach to identify SAP-dependent developmental checkpoints and to define the SAP-dependent γδ TCR repertoire in mice. SAP deficiency resulted in both a significant loss of an immature Gzma+Blk+Etv5+Tox2+ γδT17 precursor population and a significant increase in Cd4+Cd8+Rorc+Ptcra+Rag1+ thymic γδ T cells. SAP-dependent diversion of embryonic day 17 thymic γδ T cell clonotypes into the αβ T cell developmental pathway was associated with a decreased frequency of mature clonotypes in neonatal thymus, and an altered γδ TCR repertoire in the periphery. Finally, we identify TRGV4/TRAV13-4(DV7)-expressing T cells as a novel, SAP-dependent Vγ4 γδT1 subset. Together, the data support a model in which SAP-dependent γδ/αβ T cell lineage commitment regulates γδ T cell developmental programming and shapes the γδ TCR repertoire. |
| format | Article |
| id | doaj-art-0c074fa78fa34bb4a64e74d5eb6fbdbd |
| institution | Kabale University |
| issn | 2050-084X |
| language | English |
| publishDate | 2024-12-01 |
| publisher | eLife Sciences Publications Ltd |
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| series | eLife |
| spelling | doaj-art-0c074fa78fa34bb4a64e74d5eb6fbdbd2024-12-10T16:42:17ZengeLife Sciences Publications LtdeLife2050-084X2024-12-011310.7554/eLife.97229SLAM/SAP signaling regulates discrete γδ T cell developmental checkpoints and shapes the innate-like γδ TCR repertoireSomen K Mistri0https://orcid.org/0000-0002-2139-6927Brianna M Hilton1https://orcid.org/0009-0001-5209-7268Katherine J Horrigan2https://orcid.org/0009-0001-3102-3315Emma S Andretta3Remi Savard4Oliver Dienz5https://orcid.org/0000-0001-9380-4873Kenneth J Hampel6Diana L Gerrard7Joshua T Rose8Nikoletta Sidiropoulos9Dev Majumdar10Jonathan E Boyson11https://orcid.org/0000-0003-2673-9148Department of Surgery, Larner College of Medicine, University of Vermont, Burlington, United StatesDepartment of Surgery, Larner College of Medicine, University of Vermont, Burlington, United StatesDepartment of Surgery, Larner College of Medicine, University of Vermont, Burlington, United StatesDepartment of Surgery, Larner College of Medicine, University of Vermont, Burlington, United StatesDepartment of Surgery, Larner College of Medicine, University of Vermont, Burlington, United StatesDepartment of Surgery, Larner College of Medicine, University of Vermont, Burlington, United StatesDepartment of Pathology and Laboratory Medicine, Larner College of Medicine, University of Vermont Medical Center, Burlington, United StatesDepartment of Pathology and Laboratory Medicine, Larner College of Medicine, University of Vermont Medical Center, Burlington, United StatesDepartment of Pathology and Laboratory Medicine, Larner College of Medicine, University of Vermont Medical Center, Burlington, United StatesDepartment of Pathology and Laboratory Medicine, Larner College of Medicine, University of Vermont Medical Center, Burlington, United StatesDepartment of Surgery, Larner College of Medicine, University of Vermont, Burlington, United StatesDepartment of Surgery, Larner College of Medicine, University of Vermont, Burlington, United StatesDuring thymic development, most γδ T cells acquire innate-like characteristics that are critical for their function in tumor surveillance, infectious disease, and tissue repair. The mechanisms, however, that regulate γδ T cell developmental programming remain unclear. Recently, we demonstrated that the SLAM/SAP signaling pathway regulates the development and function of multiple innate-like γδ T cell subsets. Here, we used a single-cell proteogenomics approach to identify SAP-dependent developmental checkpoints and to define the SAP-dependent γδ TCR repertoire in mice. SAP deficiency resulted in both a significant loss of an immature Gzma+Blk+Etv5+Tox2+ γδT17 precursor population and a significant increase in Cd4+Cd8+Rorc+Ptcra+Rag1+ thymic γδ T cells. SAP-dependent diversion of embryonic day 17 thymic γδ T cell clonotypes into the αβ T cell developmental pathway was associated with a decreased frequency of mature clonotypes in neonatal thymus, and an altered γδ TCR repertoire in the periphery. Finally, we identify TRGV4/TRAV13-4(DV7)-expressing T cells as a novel, SAP-dependent Vγ4 γδT1 subset. Together, the data support a model in which SAP-dependent γδ/αβ T cell lineage commitment regulates γδ T cell developmental programming and shapes the γδ TCR repertoire.https://elifesciences.org/articles/97229gamma delta T cellsT cellsthymic development |
| spellingShingle | Somen K Mistri Brianna M Hilton Katherine J Horrigan Emma S Andretta Remi Savard Oliver Dienz Kenneth J Hampel Diana L Gerrard Joshua T Rose Nikoletta Sidiropoulos Dev Majumdar Jonathan E Boyson SLAM/SAP signaling regulates discrete γδ T cell developmental checkpoints and shapes the innate-like γδ TCR repertoire eLife gamma delta T cells T cells thymic development |
| title | SLAM/SAP signaling regulates discrete γδ T cell developmental checkpoints and shapes the innate-like γδ TCR repertoire |
| title_full | SLAM/SAP signaling regulates discrete γδ T cell developmental checkpoints and shapes the innate-like γδ TCR repertoire |
| title_fullStr | SLAM/SAP signaling regulates discrete γδ T cell developmental checkpoints and shapes the innate-like γδ TCR repertoire |
| title_full_unstemmed | SLAM/SAP signaling regulates discrete γδ T cell developmental checkpoints and shapes the innate-like γδ TCR repertoire |
| title_short | SLAM/SAP signaling regulates discrete γδ T cell developmental checkpoints and shapes the innate-like γδ TCR repertoire |
| title_sort | slam sap signaling regulates discrete γδ t cell developmental checkpoints and shapes the innate like γδ tcr repertoire |
| topic | gamma delta T cells T cells thymic development |
| url | https://elifesciences.org/articles/97229 |
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