CD44 acts as a co-receptor to confer cell type-specific enhancement of signaling and regulatory T cell induction by TGM-1, a helminth parasite mimic of TGF

ABSTRACT: Long-lived parasites evade host immunity through highly evolved molecular strategies. The murine intestinal helminth, Heligmosomoides polygyrus, suppresses the host immune system through release of an immunoregulatory TGF-β mimic, TGM-1, which is a divergent member of the CCP (Sushi) protein family. TGM-1 comprises 5 domains, of which domains 1-3 (D1/2/3) bind mammalian TGFβ 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 a truncated TGM-1, lacking these domains, showed reduced potency. Combination of D1/2/3 and D4/5 as separate proteins did not restore full potency, suggesting that a physical linkage is required, and that these domains may not deliver an independent signal. Co-precipitation from cells treated with biotinylated D4/5, followed by mass spectrometry, identified the cell surface protein CD44 as a co-receptor for TGM-1. Both full-length and D4/5 bound strongly to a range of primary cells and cell lines, while D1/2/3 binding was only marginally detectable. Ectopic expression of CD44 in non responding cells conferred responsiveness, while specific genetic depletion of CD44 abolished the enhancement effect of D4/5, and ablated the ability of full-length TGM-1 to bind to cell surfaces. Moreover, CD44-deficient T cells showed attenuated induction of Foxp3 by full-length TGM-1, to levels similar to 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.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Cell Culture

SUBMITTER: Román González-Prieto  

LAB HEAD: Román González-Prieto

PROVIDER: PXD037799 | Pride | 2023-10-24

REPOSITORIES: Pride