The schistosome oligosaccharide lacto-N-neotetraose expands Gr1(+) cells that secrete anti-inflammatory cytokines and inhibit proliferation of naive CD4(+) cells: A potential mechanism for immune polarization in helminth infections

Immunomodulatory oligosaccharides found on helminths also are found in huma n milk, and both helminths and milk have been shown to be immunosuppressive . We have been examining the immunomodulatory capabilities of two oligosacc harides expressed in milk and on helminth parasites, lacto-N-fucopentaose I II and facto-N-neotetraose (LNnT). In an attempt to dissect mechanisms that lead to Th2 polarization and immune suppression, we examined the early res ponse in mice to the glycoconjugate LNnT-Dextran (LNnT-Dex). We found that injection of LNnT-Dex expanded a cell population, phenotypically defined as Gr1*/CD11b(+)/F4/80(+), as early as 2 h after injection. Examination of sp ontaneous cytokine production showed that this Gr1(+)/F4/80(+) population o f cells spontaneously produced low levels of proinflammatory cytokines, but higher levels of IL-10 and TGF-beta ex vivo, compared to peritoneal cells from mice injected with Dex. Gr1(+) cells adoptively suppressed naive CD4() T cell proliferation in vitro in response to anti-CD3/CD28 Ab stimulation . Suppression of naive CD4(+) cells involved cell contact and was dependent on IFN-gamma and NO, with a discrete role played by IL-10. Coculture of na ive CD4(+)T cells with Gr1(+) suppressor cells did not lead to CD4(+) T cel l apoptosis, although it did imprint on naive CD4(+) T cells a response cha racterized by lower levels of IFN-gamma, coincident with increased IL-13 pr oduction. Our results suggest that both human milk and helminth parasites m ay share a ligand-specific mechanism involved in the generation of anti-inf lammatory mediators that suppress Th1-type and inflammatory responses.