A schistosome-expressed immunomodulatory glycoconjugate expands peritonealGr1(+) macrophages that suppress naive CD4(+) T cell proliferation via an IFN-gamma and nitric oxide-dependent mechanism

Lacto-N-fucopentaose III (LNFPIII) is found in human milk and on the Th2 dr iving helminth parasite Schistosoma mansoni. This pentasaccharide drives Th 2-type responses in vivo and in vitro when conjugated to a carrier. In an a ttempt to further understand early events in Th1 to Th2 switching, we exami ned phenotypic and functional changes in peritoneal cell populations in BAL B/c and SCID mice following LNFPIII-dextran injection. We found that i.p. i njection with LNFPIII-dextran resulted in rapid (< 20 h) expansion of the G r1(+) subpopulation of F4/80(+)/CD11b(+) peritoneal cells, comprising up to 75% of F4/80(+)/CD11b(+) peritoneal cells compared with 18% in uninjected or dextran-injected mice. Functionally, these cells suppressed anti-CD3- an d anti-CD28-induced proliferation of naive CD4(+) T cells. LNFPIII-dextran also expanded functional Gr1(+) suppressor macrophages in SCID mice, demons trating that expansion and function of suppressor cells did not require T c ells. Suppression in both BALB/c and SCID mice was NO and IFN-gamma depende nt, as addition of inhibitors of inducible NO Synthase (N-G-monomethyl-L-ar ginine), as well as anti-IFN-gamma Abs, restored the ability of CD4(+) T ce lls to proliferate in vitro. Depletion of the F4/80(+) subset of Gr1(+) cel ls eliminated the suppressive activity of peritoneal exudate cells showing that these cells were macrophages. Thus, LNFPIII-dextran rapidly expands th e Gr1(+) suppressor macrophage population in the peritoneal cavities of oth erwise naive mice. These Gr1(+) cells suppress proliferation of naive CD4() T cells in an NO-dependent mechanism, and may play a regulatory role in t he switching of Th1(-) to Th2-type responses.