Dendritic cell-expressed common gamma-chain recruits IL-15 for trans-presentation at the murine immunological synapse
<h4>Background</h4> <p>Mutations of the common cytokine receptor gamma chain (γc) cause Severe Combined Immunodeficiency characterized by absent T and NK cell development. Although stem cell therapy restores these lineages, residual immune defects are observed that may result from...
| Main Authors: | , , , , , , , , , , |
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| Format: | Journal article |
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Wellcome Trust
2017
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| _version_ | 1797097972437090304 |
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| author | Beilin, C Choudhuri, K Bouma, G Malinova, D Llodra, J Stokes, D Shimaoka, M Springer, T Dustin, M Thrasher, A Burns, S |
| author_facet | Beilin, C Choudhuri, K Bouma, G Malinova, D Llodra, J Stokes, D Shimaoka, M Springer, T Dustin, M Thrasher, A Burns, S |
| author_sort | Beilin, C |
| collection | OXFORD |
| description | <h4>Background</h4> <p>Mutations of the common cytokine receptor gamma chain (γc) cause Severe Combined Immunodeficiency characterized by absent T and NK cell development. Although stem cell therapy restores these lineages, residual immune defects are observed that may result from selective persistence of γc-deficiency in myeloid lineages. However, little is known about the contribution of myeloid-expressed γc to protective immune responses. Here we examine the importance of γc for myeloid dendritic cell (DC) function.</p> <h4>Methods</h4> <p>We utilize a combination of in vitro DC/T-cell co-culture assays and a novel lipid bilayer system mimicking the T cell surface to delineate the role of DC-expressed γc during DC/T-cell interaction.</p> <h4>Results</h4> <p>We observed that γc in DC was recruited to the contact interface following MHCII ligation, and promoted IL-15Rα colocalization with engaged MHCII. Unexpectedly, trans-presentation of IL-15 was required for optimal CD4+T cell activation by DC and depended on DC γc expression. Neither recruitment of IL-15Rα nor IL-15 trans-signaling at the DC immune synapse (IS), required γc signaling in DC, suggesting that γc facilitates IL-15 transpresentation through induced intermolecular cis associations or cytoskeletal reorganization following MHCII ligation.</p> <h4>Conclusions</h4> <p>These findings show that DC-expressed γc is required for effective antigen-induced CD4+ T cell activation. We reveal a novel mechanism for recruitment of DC IL-15/IL-15Rα complexes to the IS, leading to CD4+ T cell costimulation through localized IL-15 transpresentation that is coordinated with antigen-recognition.</p> |
| first_indexed | 2024-03-07T05:02:58Z |
| format | Journal article |
| id | oxford-uuid:d8f35139-9617-4c91-bf1f-bacb2f4f4722 |
| institution | University of Oxford |
| last_indexed | 2024-03-07T05:02:58Z |
| publishDate | 2017 |
| publisher | Wellcome Trust |
| record_format | dspace |
| spelling | oxford-uuid:d8f35139-9617-4c91-bf1f-bacb2f4f47222022-03-27T08:52:30ZDendritic cell-expressed common gamma-chain recruits IL-15 for trans-presentation at the murine immunological synapseJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:d8f35139-9617-4c91-bf1f-bacb2f4f4722Symplectic Elements at OxfordWellcome Trust2017Beilin, CChoudhuri, KBouma, GMalinova, DLlodra, JStokes, DShimaoka, MSpringer, TDustin, MThrasher, ABurns, S <h4>Background</h4> <p>Mutations of the common cytokine receptor gamma chain (γc) cause Severe Combined Immunodeficiency characterized by absent T and NK cell development. Although stem cell therapy restores these lineages, residual immune defects are observed that may result from selective persistence of γc-deficiency in myeloid lineages. However, little is known about the contribution of myeloid-expressed γc to protective immune responses. Here we examine the importance of γc for myeloid dendritic cell (DC) function.</p> <h4>Methods</h4> <p>We utilize a combination of in vitro DC/T-cell co-culture assays and a novel lipid bilayer system mimicking the T cell surface to delineate the role of DC-expressed γc during DC/T-cell interaction.</p> <h4>Results</h4> <p>We observed that γc in DC was recruited to the contact interface following MHCII ligation, and promoted IL-15Rα colocalization with engaged MHCII. Unexpectedly, trans-presentation of IL-15 was required for optimal CD4+T cell activation by DC and depended on DC γc expression. Neither recruitment of IL-15Rα nor IL-15 trans-signaling at the DC immune synapse (IS), required γc signaling in DC, suggesting that γc facilitates IL-15 transpresentation through induced intermolecular cis associations or cytoskeletal reorganization following MHCII ligation.</p> <h4>Conclusions</h4> <p>These findings show that DC-expressed γc is required for effective antigen-induced CD4+ T cell activation. We reveal a novel mechanism for recruitment of DC IL-15/IL-15Rα complexes to the IS, leading to CD4+ T cell costimulation through localized IL-15 transpresentation that is coordinated with antigen-recognition.</p> |
| spellingShingle | Beilin, C Choudhuri, K Bouma, G Malinova, D Llodra, J Stokes, D Shimaoka, M Springer, T Dustin, M Thrasher, A Burns, S Dendritic cell-expressed common gamma-chain recruits IL-15 for trans-presentation at the murine immunological synapse |
| title | Dendritic cell-expressed common gamma-chain recruits IL-15 for trans-presentation at the murine immunological synapse |
| title_full | Dendritic cell-expressed common gamma-chain recruits IL-15 for trans-presentation at the murine immunological synapse |
| title_fullStr | Dendritic cell-expressed common gamma-chain recruits IL-15 for trans-presentation at the murine immunological synapse |
| title_full_unstemmed | Dendritic cell-expressed common gamma-chain recruits IL-15 for trans-presentation at the murine immunological synapse |
| title_short | Dendritic cell-expressed common gamma-chain recruits IL-15 for trans-presentation at the murine immunological synapse |
| title_sort | dendritic cell expressed common gamma chain recruits il 15 for trans presentation at the murine immunological synapse |
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