van Dinther, M. et al. (2023) CD44 acts as a co-receptor for cell-specific enhancement of signaling and regulatory T cell induction by TGM1, a parasite TGF-β mimic. Proceedings of the National Academy of Sciences of the United States of America, 120(34), e230237012. (doi: 10.1073/pnas.2302370120) (PMID:37590410) (PMCID:PMC10450677)
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Abstract
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.
| Item Type: | Articles |
|---|---|
| Additional Information: | This work was supported by the Wellcome Trust through an Investigator Award to RMM (Ref 219530), and core-funded Wellcome Centre for Integrative Parasitology (Ref: 104111); by the NIH through an RO3 award to AH (AI153915) and an F30 award to AM (AI57069). |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | White, Dr Madeleine and Singh, Dr Shashi and Maizels, Professor Rick and Cunningham, Dr Kyle and Campion, Ms Tiffany and Ciancia, Miss Claire |
| Authors: | van Dinther, M., Cunningham, K. T., Singh, S. P., White, M. P.J., Campion, T., Ciancia, C., van Veelen, P. A., de Ru, A. H., González-Prieto, R., Mukundan, A., Byeon, C.-H., Staggers, S. R., Hinck, C. S., Hinck, A. P., Dijke, P. t., and Maizels, R. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Infection & Immunity |
| Journal Name: | Proceedings of the National Academy of Sciences of the United States of America |
| Publisher: | National Academy of Sciences |
| ISSN: | 0027-8424 |
| ISSN (Online): | 1091-6490 |
| Copyright Holders: | Copyright © 2023 The Author(s) |
| First Published: | First published in PNAS 120(34):e2302370120 |
| Publisher Policy: | Reproduced under a Creative Commons licence |
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