DOCK2 Sets the Threshold for Entry into the Virtual Memory CD8 + T Cell Compartment by Negatively Regulating Tonic TCR Triggering
Copyright © 2019 by The American Association of Immunologists, Inc. The control of cytoskeletal dynamics by dedicator of cytokinesis 2 (DOCK2), a hematopoietic cell-specific actin effector protein, has been implicated in TCR signaling and T cell migration. Biallelic mutations in Dock2 have been iden...
| Main Authors: | , , , , , , , , , , |
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| Other Authors: | |
| Format: | Article |
| Language: | English |
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The American Association of Immunologists
2021
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| Online Access: | https://hdl.handle.net/1721.1/136611 |
| _version_ | 1811090526016897024 |
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| author | Mahajan, Vinay S Demissie, Ezana Alsufyani, Faisal Kumari, Sudha Yuen, Grace J Viswanadham, Vinayak Huang, Andrew Tran, Johnson Q Moon, James J Irvine, Darrell J Pillai, Shiv |
| author2 | Koch Institute for Integrative Cancer Research at MIT |
| author_facet | Koch Institute for Integrative Cancer Research at MIT Mahajan, Vinay S Demissie, Ezana Alsufyani, Faisal Kumari, Sudha Yuen, Grace J Viswanadham, Vinayak Huang, Andrew Tran, Johnson Q Moon, James J Irvine, Darrell J Pillai, Shiv |
| author_sort | Mahajan, Vinay S |
| collection | MIT |
| description | Copyright © 2019 by The American Association of Immunologists, Inc. The control of cytoskeletal dynamics by dedicator of cytokinesis 2 (DOCK2), a hematopoietic cell-specific actin effector protein, has been implicated in TCR signaling and T cell migration. Biallelic mutations in Dock2 have been identified in patients with a recessive form of combined immunodeficiency with defects in T, B, and NK cell activation. Surprisingly, we show in this study that certain immune functions of CD8+ T cells are enhanced in the absence of DOCK2. Dock2-deficient mice have a pronounced expansion of their memory T cell compartment. Bone marrow chimera and adoptive transfer studies indicate that these memory T cells develop in a cell-intrinsic manner following thymic egress. Transcriptional profiling, TCR repertoire analyses, and cell surface marker expression indicate that Dock2-deficient naive CD8+ T cells directly convert into virtual memory cells without clonal effector T cell expansion. This direct conversion to memory is associated with a selective increase in TCR sensitivity to self-peptide MHC in vivo and an enhanced response to weak agonist peptides ex vivo. In contrast, the response to strong agonist peptides remains unaltered in Dock2-deficient T cells. Collectively, these findings suggest that the regulation of the actin dynamics by DOCK2 enhances the threshold for entry into the virtual memory compartment by negatively regulating tonic TCR triggering in response to weak agonists. |
| first_indexed | 2024-09-23T14:47:33Z |
| format | Article |
| id | mit-1721.1/136611 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T14:47:33Z |
| publishDate | 2021 |
| publisher | The American Association of Immunologists |
| record_format | dspace |
| spelling | mit-1721.1/1366112023-09-19T18:27:02Z DOCK2 Sets the Threshold for Entry into the Virtual Memory CD8 + T Cell Compartment by Negatively Regulating Tonic TCR Triggering Mahajan, Vinay S Demissie, Ezana Alsufyani, Faisal Kumari, Sudha Yuen, Grace J Viswanadham, Vinayak Huang, Andrew Tran, Johnson Q Moon, James J Irvine, Darrell J Pillai, Shiv Koch Institute for Integrative Cancer Research at MIT Copyright © 2019 by The American Association of Immunologists, Inc. The control of cytoskeletal dynamics by dedicator of cytokinesis 2 (DOCK2), a hematopoietic cell-specific actin effector protein, has been implicated in TCR signaling and T cell migration. Biallelic mutations in Dock2 have been identified in patients with a recessive form of combined immunodeficiency with defects in T, B, and NK cell activation. Surprisingly, we show in this study that certain immune functions of CD8+ T cells are enhanced in the absence of DOCK2. Dock2-deficient mice have a pronounced expansion of their memory T cell compartment. Bone marrow chimera and adoptive transfer studies indicate that these memory T cells develop in a cell-intrinsic manner following thymic egress. Transcriptional profiling, TCR repertoire analyses, and cell surface marker expression indicate that Dock2-deficient naive CD8+ T cells directly convert into virtual memory cells without clonal effector T cell expansion. This direct conversion to memory is associated with a selective increase in TCR sensitivity to self-peptide MHC in vivo and an enhanced response to weak agonist peptides ex vivo. In contrast, the response to strong agonist peptides remains unaltered in Dock2-deficient T cells. Collectively, these findings suggest that the regulation of the actin dynamics by DOCK2 enhances the threshold for entry into the virtual memory compartment by negatively regulating tonic TCR triggering in response to weak agonists. 2021-10-27T20:36:13Z 2021-10-27T20:36:13Z 2020 2021-02-03T14:46:36Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/136611 en 10.4049/JIMMUNOL.1900440 Journal of immunology Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf The American Association of Immunologists PMC |
| spellingShingle | Mahajan, Vinay S Demissie, Ezana Alsufyani, Faisal Kumari, Sudha Yuen, Grace J Viswanadham, Vinayak Huang, Andrew Tran, Johnson Q Moon, James J Irvine, Darrell J Pillai, Shiv DOCK2 Sets the Threshold for Entry into the Virtual Memory CD8 + T Cell Compartment by Negatively Regulating Tonic TCR Triggering |
| title | DOCK2 Sets the Threshold for Entry into the Virtual Memory CD8 + T Cell Compartment by Negatively Regulating Tonic TCR Triggering |
| title_full | DOCK2 Sets the Threshold for Entry into the Virtual Memory CD8 + T Cell Compartment by Negatively Regulating Tonic TCR Triggering |
| title_fullStr | DOCK2 Sets the Threshold for Entry into the Virtual Memory CD8 + T Cell Compartment by Negatively Regulating Tonic TCR Triggering |
| title_full_unstemmed | DOCK2 Sets the Threshold for Entry into the Virtual Memory CD8 + T Cell Compartment by Negatively Regulating Tonic TCR Triggering |
| title_short | DOCK2 Sets the Threshold for Entry into the Virtual Memory CD8 + T Cell Compartment by Negatively Regulating Tonic TCR Triggering |
| title_sort | dock2 sets the threshold for entry into the virtual memory cd8 t cell compartment by negatively regulating tonic tcr triggering |
| url | https://hdl.handle.net/1721.1/136611 |
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