A schistosome-expressed immunomodulatory glycoconjugate expands peritoneal Gr1(+) 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 driving helminth parasite Schistosoma mansoni. This pentasaccharide drives Th2-type responses in vivo and in vitro when conjugated to a carrier. In an attempt to further understand early events in Th1 to Th2 switching, we examined phenotypic and functional changes in peritoneal cell populations in BALB/c and SCID mice following LNFPIII-dextran injection. We found that i.p. injection with LNFPIII-dextran resulted in rapid (<20 h) expansion of the Gr1(+) 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- and anti-CD28-induced proliferation of naive CD4(+) T cells. LNFPIII-dextran also expanded functional Gr1(+) suppressor macrophages in SCID mice, demonstrating that expansion and function of suppressor cells did not require T cells. Suppression in both BALB/c and SCID mice was NO and IFN-gamma dependent, as addition of inhibitors of inducible NO synthase (N(G)-monomethyl-L-arginine), as well as anti-IFN-gamma Abs, restored the ability of CD4(+) T cells to proliferate in vitro. Depletion of the F4/80(+) subset of Gr1(+) cells eliminated the suppressive activity of peritoneal exudate cells showing that these cells were macrophages. Thus, LNFPIII-dextran rapidly expands the Gr1(+) suppressor macrophage population in the peritoneal cavities of otherwise naive mice. These Gr1(+) cells suppress proliferation of naive CD4(+) T cells in an NO-dependent mechanism, and may play a regulatory role in the switching of Th1- to Th2-type responses.
Atochina
O
O
Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115, USA. oatochin@hsph.harvard.edu
Daly-Engel
T
T
Piskorska
D
D
McGuire
E
E
Harn
D A
DA
D000606:Amino Sugars / Q000276:immunology*; D000818:Animals; D000943:Antigens, Differentiation; D000947:Antigens, Helminth / Q000276:immunology*; D018106:CD28 Antigens; D017252:CD3 Complex; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002455:Cell Division; D007166:Immunosuppressive Agents / Q000276:immunology*; D007371:Interferon-gamma / Q000378:metabolism; D008213:Lymphocyte Activation; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D009569:Nitric Oxide / Q000378:metabolism; D011134:Polysaccharides / Q000276:immunology*; D012550:Schistosoma mansoni / Q000276:immunology*; D015398:Signal Transduction
D000606:Amino Sugars; D000943:Antigens, Differentiation; D000947:Antigens, Helminth; D018106:CD28 Antigens; D017252:CD3 Complex; D007166:Immunosuppressive Agents; D011134:Polysaccharides; C434666:lacto-N-fucopentaose III; D009569:Nitric Oxide; D007371:Interferon-gamma