CD44 Acts as a Coreceptor for Cell-specific Enhancement of Signaling and Regulatory T Cell Induction by TGM1, a Parasite TGF-β Mimic
Long-lived parasites evade host immunity through highly evolved molecular strategies. The murine intestinal helminth, Heligmosomoides polygyrus, down-modulates the host immune system through release of an immunosuppressive TGF-β mimic, TGM1, which is a divergent member of the CCP (Sushi) protein fam...
| Autores: | , , , , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2023 |
| País: | España |
| Institución: | Universidad de Sevilla (US) |
| Repositorio: | idUS. Depósito de Investigación de la Universidad de Sevilla |
| OAI Identifier: | oai:idus.us.es:11441/155242 |
| Acceso en línea: | https://hdl.handle.net/11441/155242 https://doi.org/10.1073/pnas.2302370120 |
| Access Level: | acceso abierto |
| Palabra clave: | Complement control protein Convergent evolution Fibroblast Heligmosomoides polygyrus T lymphocyte |
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CD44 Acts as a Coreceptor for Cell-specific Enhancement of Signaling and Regulatory T Cell Induction by TGM1, a Parasite TGF-β Mimicvan Dinther, MaartenCunningham, Kyle T.Singh, Shashi PrakashWhite, Madeleine P.J.Campion, TiffanyCiancia, Clairevan Veelen, Peter A.de Ru, Arnoud H.González Prieto, RománMukundan, AnanyaMaizels, Rick M.Complement control proteinConvergent evolutionFibroblastHeligmosomoides polygyrusT lymphocyteLong-lived parasites evade host immunity through highly evolved molecular strategies. The murine intestinal helminth, Heligmosomoides polygyrus, down-modulates the host immune system through release of an immunosuppressive TGF-β mimic, TGM1, which is a divergent member of the CCP (Sushi) protein family. TGM1 comprises 5 domains, of which domains 1-3 (D1/2/3) bind mammalian TGF-β receptors, acting on T cells to induce Foxp3+ regulatory T cells; however, the roles of domains 4 and 5 (D4/5) remain unknown. We noted that truncated TGM1, lacking D4/5, showed reduced potency. Combination of D1/2/3 and D4/5 as separate proteins did not alter potency, suggesting that a physical linkage is required and that these domains do not deliver an independent signal. Coprecipitation from cells treated with biotinylated D4/5, followed by mass spectrometry, identified the cell surface protein CD44 as a coreceptor for TGM1. Both full-length and D4/5 bound strongly to a range of primary cells and cell lines, to a greater degree than D1/2/3 alone, although some cell lines did not respond to TGM1. Ectopic expression of CD44 in nonresponding cells conferred responsiveness, while genetic depletion of CD44 abolished enhancement by D4/5 and ablated the ability of full-length TGM1 to bind to cell surfaces. Moreover, CD44-deficient T cells showed attenuated induction of Foxp3 by full-length TGM1, to levels similar to those induced by D1/2/3. Hence, a parasite protein known to bind two host cytokine receptor subunits has evolved a third receptor specificity, which serves to raise the avidity and cell type–specific potency of TGF-β signaling in mammalian cells.Wellcome Trust 219530Wellcome Centre for Integrative Parasitology 10411National Institutes of Health AI153915, AI57069National Academy of SciencesBiología CelularWellcome Trust. Reino Unido.Wellcome Centre for Integrative Parasitology. Reino Unido.National Institutes of Health (NIH). EE.UU.2023info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttps://hdl.handle.net/11441/155242https://doi.org/10.1073/pnas.2302370120reponame:idUS. Depósito de Investigación de la Universidad de Sevillainstname:Universidad de Sevilla (US)InglésProceedings of the National Academy of Sciences of the United States of America, 120 (34), e2302370120.21953010411AI153915AI57069https://dx.doi.org/10.1073/pnas.2302370120info:eu-repo/semantics/openAccessoai:idus.us.es:11441/1552422026-06-17T12:51:07Z |
| dc.title.none.fl_str_mv |
CD44 Acts as a Coreceptor for Cell-specific Enhancement of Signaling and Regulatory T Cell Induction by TGM1, a Parasite TGF-β Mimic |
| title |
CD44 Acts as a Coreceptor for Cell-specific Enhancement of Signaling and Regulatory T Cell Induction by TGM1, a Parasite TGF-β Mimic |
| spellingShingle |
CD44 Acts as a Coreceptor for Cell-specific Enhancement of Signaling and Regulatory T Cell Induction by TGM1, a Parasite TGF-β Mimic van Dinther, Maarten Complement control protein Convergent evolution Fibroblast Heligmosomoides polygyrus T lymphocyte |
| title_short |
CD44 Acts as a Coreceptor for Cell-specific Enhancement of Signaling and Regulatory T Cell Induction by TGM1, a Parasite TGF-β Mimic |
| title_full |
CD44 Acts as a Coreceptor for Cell-specific Enhancement of Signaling and Regulatory T Cell Induction by TGM1, a Parasite TGF-β Mimic |
| title_fullStr |
CD44 Acts as a Coreceptor for Cell-specific Enhancement of Signaling and Regulatory T Cell Induction by TGM1, a Parasite TGF-β Mimic |
| title_full_unstemmed |
CD44 Acts as a Coreceptor for Cell-specific Enhancement of Signaling and Regulatory T Cell Induction by TGM1, a Parasite TGF-β Mimic |
| title_sort |
CD44 Acts as a Coreceptor for Cell-specific Enhancement of Signaling and Regulatory T Cell Induction by TGM1, a Parasite TGF-β Mimic |
| dc.creator.none.fl_str_mv |
van Dinther, Maarten Cunningham, Kyle T. Singh, Shashi Prakash White, Madeleine P.J. Campion, Tiffany Ciancia, Claire van Veelen, Peter A. de Ru, Arnoud H. González Prieto, Román Mukundan, Ananya Maizels, Rick M. |
| author |
van Dinther, Maarten |
| author_facet |
van Dinther, Maarten Cunningham, Kyle T. Singh, Shashi Prakash White, Madeleine P.J. Campion, Tiffany Ciancia, Claire van Veelen, Peter A. de Ru, Arnoud H. González Prieto, Román Mukundan, Ananya Maizels, Rick M. |
| author_role |
author |
| author2 |
Cunningham, Kyle T. Singh, Shashi Prakash White, Madeleine P.J. Campion, Tiffany Ciancia, Claire van Veelen, Peter A. de Ru, Arnoud H. González Prieto, Román Mukundan, Ananya Maizels, Rick M. |
| author2_role |
author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Biología Celular Wellcome Trust. Reino Unido. Wellcome Centre for Integrative Parasitology. Reino Unido. National Institutes of Health (NIH). EE.UU. |
| dc.subject.none.fl_str_mv |
Complement control protein Convergent evolution Fibroblast Heligmosomoides polygyrus T lymphocyte |
| topic |
Complement control protein Convergent evolution Fibroblast Heligmosomoides polygyrus T lymphocyte |
| description |
Long-lived parasites evade host immunity through highly evolved molecular strategies. The murine intestinal helminth, Heligmosomoides polygyrus, down-modulates the host immune system through release of an immunosuppressive TGF-β mimic, TGM1, which is a divergent member of the CCP (Sushi) protein family. TGM1 comprises 5 domains, of which domains 1-3 (D1/2/3) bind mammalian TGF-β receptors, acting on T cells to induce Foxp3+ regulatory T cells; however, the roles of domains 4 and 5 (D4/5) remain unknown. We noted that truncated TGM1, lacking D4/5, showed reduced potency. Combination of D1/2/3 and D4/5 as separate proteins did not alter potency, suggesting that a physical linkage is required and that these domains do not deliver an independent signal. Coprecipitation from cells treated with biotinylated D4/5, followed by mass spectrometry, identified the cell surface protein CD44 as a coreceptor for TGM1. Both full-length and D4/5 bound strongly to a range of primary cells and cell lines, to a greater degree than D1/2/3 alone, although some cell lines did not respond to TGM1. Ectopic expression of CD44 in nonresponding cells conferred responsiveness, while genetic depletion of CD44 abolished enhancement by D4/5 and ablated the ability of full-length TGM1 to bind to cell surfaces. Moreover, CD44-deficient T cells showed attenuated induction of Foxp3 by full-length TGM1, to levels similar to those induced by D1/2/3. Hence, a parasite protein known to bind two host cytokine receptor subunits has evolved a third receptor specificity, which serves to raise the avidity and cell type–specific potency of TGF-β signaling in mammalian cells. |
| publishDate |
2023 |
| dc.date.none.fl_str_mv |
2023 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion |
| format |
article |
| status_str |
publishedVersion |
| dc.identifier.none.fl_str_mv |
https://hdl.handle.net/11441/155242 https://doi.org/10.1073/pnas.2302370120 |
| url |
https://hdl.handle.net/11441/155242 https://doi.org/10.1073/pnas.2302370120 |
| dc.language.none.fl_str_mv |
Inglés |
| language_invalid_str_mv |
Inglés |
| dc.relation.none.fl_str_mv |
Proceedings of the National Academy of Sciences of the United States of America, 120 (34), e2302370120. 219530 10411 AI153915 AI57069 https://dx.doi.org/10.1073/pnas.2302370120 |
| dc.rights.none.fl_str_mv |
info:eu-repo/semantics/openAccess |
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openAccess |
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application/pdf application/pdf |
| dc.publisher.none.fl_str_mv |
National Academy of Sciences |
| publisher.none.fl_str_mv |
National Academy of Sciences |
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reponame:idUS. Depósito de Investigación de la Universidad de Sevilla instname:Universidad de Sevilla (US) |
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Universidad de Sevilla (US) |
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idUS. Depósito de Investigación de la Universidad de Sevilla |
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idUS. Depósito de Investigación de la Universidad de Sevilla |
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