PTPN22 R620W gene editing in T cells enhances low-avidity TCR responses
A genetic variant in the gene PTPN22 (R620W, rs2476601) is strongly associated with increased risk for multiple autoimmune diseases and linked to altered TCR regulation and T cell activation. Here, we utilize Crispr/Cas9 gene editing with donor DNA repair templates in human cord blood-derived, naive...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2023-03-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/81577 |
| _version_ | 1797854790438354944 |
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| author | Warren Anderson Fariba Barahmand-pour-Whitman Peter S Linsley Karen Cerosaletti Jane H Buckner David J Rawlings |
| author_facet | Warren Anderson Fariba Barahmand-pour-Whitman Peter S Linsley Karen Cerosaletti Jane H Buckner David J Rawlings |
| author_sort | Warren Anderson |
| collection | DOAJ |
| description | A genetic variant in the gene PTPN22 (R620W, rs2476601) is strongly associated with increased risk for multiple autoimmune diseases and linked to altered TCR regulation and T cell activation. Here, we utilize Crispr/Cas9 gene editing with donor DNA repair templates in human cord blood-derived, naive T cells to generate PTPN22 risk edited (620W), non-risk edited (620R), or knockout T cells from the same donor. PTPN22 risk edited cells exhibited increased activation marker expression following non-specific TCR engagement, findings that mimicked PTPN22 KO cells. Next, using lentiviral delivery of T1D patient-derived TCRs against the pancreatic autoantigen, islet-specific glucose-6 phosphatase catalytic subunit-related protein (IGRP), we demonstrate that loss of PTPN22 function led to enhanced signaling in T cells expressing a lower avidity self-reactive TCR, but not a high-avidity TCR. In this setting, loss of PTPN22 mediated enhanced proliferation and Th1 skewing. Importantly, expression of the risk variant in association with a lower avidity TCR also increased proliferation relative to PTPN22 non-risk T cells. Together, these findings suggest that, in primary human T cells, PTPN22 rs2476601 contributes to autoimmunity risk by permitting increased TCR signaling and activation in mildly self-reactive T cells, thereby potentially expanding the self-reactive T cell pool and skewing this population toward an inflammatory phenotype. |
| first_indexed | 2024-04-09T20:12:58Z |
| format | Article |
| id | doaj.art-3e6736e42d8c4ec0adf0ff3beeb58b90 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-09T20:12:58Z |
| publishDate | 2023-03-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-3e6736e42d8c4ec0adf0ff3beeb58b902023-03-31T16:02:26ZengeLife Sciences Publications LtdeLife2050-084X2023-03-011210.7554/eLife.81577PTPN22 R620W gene editing in T cells enhances low-avidity TCR responsesWarren Anderson0https://orcid.org/0000-0002-9315-5233Fariba Barahmand-pour-Whitman1Peter S Linsley2https://orcid.org/0000-0002-8960-4307Karen Cerosaletti3https://orcid.org/0000-0002-7403-6239Jane H Buckner4David J Rawlings5https://orcid.org/0000-0002-0810-1776Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, United StatesBenaroya Research Institute at Virginia Mason, Seattle, United StatesBenaroya Research Institute at Virginia Mason, Seattle, United StatesBenaroya Research Institute at Virginia Mason, Seattle, United StatesBenaroya Research Institute at Virginia Mason, Seattle, United StatesDepartment of Pediatrics and Immunology, University of Washington, Seattle, United StatesA genetic variant in the gene PTPN22 (R620W, rs2476601) is strongly associated with increased risk for multiple autoimmune diseases and linked to altered TCR regulation and T cell activation. Here, we utilize Crispr/Cas9 gene editing with donor DNA repair templates in human cord blood-derived, naive T cells to generate PTPN22 risk edited (620W), non-risk edited (620R), or knockout T cells from the same donor. PTPN22 risk edited cells exhibited increased activation marker expression following non-specific TCR engagement, findings that mimicked PTPN22 KO cells. Next, using lentiviral delivery of T1D patient-derived TCRs against the pancreatic autoantigen, islet-specific glucose-6 phosphatase catalytic subunit-related protein (IGRP), we demonstrate that loss of PTPN22 function led to enhanced signaling in T cells expressing a lower avidity self-reactive TCR, but not a high-avidity TCR. In this setting, loss of PTPN22 mediated enhanced proliferation and Th1 skewing. Importantly, expression of the risk variant in association with a lower avidity TCR also increased proliferation relative to PTPN22 non-risk T cells. Together, these findings suggest that, in primary human T cells, PTPN22 rs2476601 contributes to autoimmunity risk by permitting increased TCR signaling and activation in mildly self-reactive T cells, thereby potentially expanding the self-reactive T cell pool and skewing this population toward an inflammatory phenotype.https://elifesciences.org/articles/81577T cellsCrisper/ Cas9transgenic TCRcord bloodPTPN22SNP |
| spellingShingle | Warren Anderson Fariba Barahmand-pour-Whitman Peter S Linsley Karen Cerosaletti Jane H Buckner David J Rawlings PTPN22 R620W gene editing in T cells enhances low-avidity TCR responses eLife T cells Crisper/ Cas9 transgenic TCR cord blood PTPN22 SNP |
| title | PTPN22 R620W gene editing in T cells enhances low-avidity TCR responses |
| title_full | PTPN22 R620W gene editing in T cells enhances low-avidity TCR responses |
| title_fullStr | PTPN22 R620W gene editing in T cells enhances low-avidity TCR responses |
| title_full_unstemmed | PTPN22 R620W gene editing in T cells enhances low-avidity TCR responses |
| title_short | PTPN22 R620W gene editing in T cells enhances low-avidity TCR responses |
| title_sort | ptpn22 r620w gene editing in t cells enhances low avidity tcr responses |
| topic | T cells Crisper/ Cas9 transgenic TCR cord blood PTPN22 SNP |
| url | https://elifesciences.org/articles/81577 |
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