Secreted and transmembrane 1A is a novel co-stimulatory ligand
Most T cell responses to pathogens or self antigens are modulated through the action of regulatory T cells and tissue-specific inhibitory mechanisms. To this end, several receptor-ligand pairs have evolved which either augment or diminish T cell function. Here we describe the tissue ligand SECTM1A (...
| Main Authors: | , , , |
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| Format: | Journal article |
| Language: | English |
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Public Library of Science
2013
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| _version_ | 1797078026286006272 |
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| author | Howie, D Garcia Rueda, H Brown, M Waldmann, H |
| author_facet | Howie, D Garcia Rueda, H Brown, M Waldmann, H |
| author_sort | Howie, D |
| collection | OXFORD |
| description | Most T cell responses to pathogens or self antigens are modulated through the action of regulatory T cells and tissue-specific inhibitory mechanisms. To this end, several receptor-ligand pairs have evolved which either augment or diminish T cell function. Here we describe the tissue ligand SECTM1A (Secreted and transmembrane1A) as an alternative murine CD7 ligand. We show that SECTM1A, like SECTM1B, binds strongly to CD7, and that SECTM1B was able to compete with SECTM1A for CD7 binding. SECTM1A is ubiquitously expressed and has two major alternative transcripts which differ in expression between tissues. Both immobilised soluble forms of SECTM1A and SECTM1B and cell surface anchored forms demonstrated opposing effects on CD4+ T cell activation. Whereas SECTM1A acted as a co-stimulator of T cells, enhancing IL-2 production and proliferation, SECTM1B proved inhibitory to TCR mediated T cell activation. Surprisingly, both functional outcomes proved to be CD7-independent, indicating the existence of alternative receptors for both ligands. We used a SECTM1A-Fc fusion protein to immunoprecipitate potential alternative ligands from detergent lysates of CD7−/− T cells and, using mass spectrometry, identified GITR as a SECTM1A binder. SECTM1A was found to bind to activated CD4+ and CD8+ T cells as well as to CHO cells expressing cell surface GITR. Binding of SECTM1A to activated primary T cells was inhibited by either GITRL-Fc or anti GITR antibodies. Thus SECTM1A and SECTM1B represent novel reciprocal alternative ligands which may function to modulate the activation of effector and regulatory T cells. The ability of SECTM1A to activate T cells may be explained by its ability to bind to GITR. |
| first_indexed | 2024-03-07T00:26:32Z |
| format | Journal article |
| id | oxford-uuid:7e54e555-3fb9-47a7-a89a-e94a8f95a416 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T00:26:32Z |
| publishDate | 2013 |
| publisher | Public Library of Science |
| record_format | dspace |
| spelling | oxford-uuid:7e54e555-3fb9-47a7-a89a-e94a8f95a4162022-03-26T21:09:30ZSecreted and transmembrane 1A is a novel co-stimulatory ligandJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:7e54e555-3fb9-47a7-a89a-e94a8f95a416EnglishSymplectic Elements at OxfordPublic Library of Science2013Howie, DGarcia Rueda, HBrown, MWaldmann, HMost T cell responses to pathogens or self antigens are modulated through the action of regulatory T cells and tissue-specific inhibitory mechanisms. To this end, several receptor-ligand pairs have evolved which either augment or diminish T cell function. Here we describe the tissue ligand SECTM1A (Secreted and transmembrane1A) as an alternative murine CD7 ligand. We show that SECTM1A, like SECTM1B, binds strongly to CD7, and that SECTM1B was able to compete with SECTM1A for CD7 binding. SECTM1A is ubiquitously expressed and has two major alternative transcripts which differ in expression between tissues. Both immobilised soluble forms of SECTM1A and SECTM1B and cell surface anchored forms demonstrated opposing effects on CD4+ T cell activation. Whereas SECTM1A acted as a co-stimulator of T cells, enhancing IL-2 production and proliferation, SECTM1B proved inhibitory to TCR mediated T cell activation. Surprisingly, both functional outcomes proved to be CD7-independent, indicating the existence of alternative receptors for both ligands. We used a SECTM1A-Fc fusion protein to immunoprecipitate potential alternative ligands from detergent lysates of CD7−/− T cells and, using mass spectrometry, identified GITR as a SECTM1A binder. SECTM1A was found to bind to activated CD4+ and CD8+ T cells as well as to CHO cells expressing cell surface GITR. Binding of SECTM1A to activated primary T cells was inhibited by either GITRL-Fc or anti GITR antibodies. Thus SECTM1A and SECTM1B represent novel reciprocal alternative ligands which may function to modulate the activation of effector and regulatory T cells. The ability of SECTM1A to activate T cells may be explained by its ability to bind to GITR. |
| spellingShingle | Howie, D Garcia Rueda, H Brown, M Waldmann, H Secreted and transmembrane 1A is a novel co-stimulatory ligand |
| title | Secreted and transmembrane 1A is a novel co-stimulatory ligand |
| title_full | Secreted and transmembrane 1A is a novel co-stimulatory ligand |
| title_fullStr | Secreted and transmembrane 1A is a novel co-stimulatory ligand |
| title_full_unstemmed | Secreted and transmembrane 1A is a novel co-stimulatory ligand |
| title_short | Secreted and transmembrane 1A is a novel co-stimulatory ligand |
| title_sort | secreted and transmembrane 1a is a novel co stimulatory ligand |
| work_keys_str_mv | AT howied secretedandtransmembrane1aisanovelcostimulatoryligand AT garciaruedah secretedandtransmembrane1aisanovelcostimulatoryligand AT brownm secretedandtransmembrane1aisanovelcostimulatoryligand AT waldmannh secretedandtransmembrane1aisanovelcostimulatoryligand |