title: Exacerbated susceptibility to infection-stimulated immunopathology in CD1d-deficient mice.
abstract: Mice lacking functional CD1d genes were used to study mechanisms of resistance to the protozoan parasite Toxoplasma gondii. Wild-type (WT) BALB/c mice, CD1d-deficient BALB/c mice, and WT C57BL/6 mice all survived an acute oral infection with a low dose of mildly virulent strain ME49 T. gondii cysts. In contrast, most CD1d-deficient C57BL/6 mice died within 2 wk of infection. Despite having parasite burdens that were only slightly higher than WT mice, CD1d-deficient C57BL/6 mice displayed greater weight loss and intestinal pathology. In C57BL/6 mice, CD4(+) cells can cause intestinal pathology during T. gondii infection. Compared with WT mice, infected CD1d-deficient C57BL/6 mice had higher frequencies and numbers of activated (CD44(high)) CD4(+) cells in mesenteric lymph nodes. Depletion of CD4(+) cells from CD1d-deficient mice reduced weight loss and prolonged survival, demonstrating a functional role for CD4(+) cells in their increased susceptibility to T. gondii infection. CD1d-deficient mice are deficient in Valpha14(+) T cells, a major population of NKT cells. Involvement of these cells in resistance to T. gondii was investigated using gene-targeted Jalpha18-deficient C57BL/6 mice, which are deficient in Valpha14(+) T cells. These mice did not succumb to acute infection, but experienced greater weight loss and more deaths than B6 mice during chronic infection, indicating that Valpha14(+) cells contribute to resistance to T. gondii. The data identify CD4(+) cells as a significant component of the marked susceptibility to T. gondii infection observed in CD1d-deficient C57BL/6 mice, and establish T. gondii as a valuable tool for deciphering CD1d-dependent protective mechanisms.
authors.affiliation: Trudeau Institute, Inc., Saranac Lake, NY 12983, USA.
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Smiley
authors.forename: Paula A
authors.initials: PA
authors.lastname: Lanthier
authors.forename: Kevin N
authors.initials: KN
authors.lastname: Couper
authors.forename: Frank M
authors.initials: FM
authors.lastname: Szaba
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Boyson
authors.forename: Wangxue
authors.initials: W
authors.lastname: Chen
authors.forename: Lawrence L
authors.initials: LL
authors.lastname: Johnson
mesh_terms: D000208:Acute Disease; D000284:Administration, Oral; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use; D018949:Antigens, CD1 / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D055610:Antigens, CD1d; D000953:Antigens, Protozoan / Q000008:administration & dosage / Q000276:immunology; D015704:CD4 Antigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000469:parasitology; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D007113:Immunity, Innate / Q000235:genetics; D007411:Intestinal Diseases, Parasitic / Q000235:genetics / Q000276:immunology / Q000473:pathology; D007413:Intestinal Mucosa / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000172:deficiency / Q000235:genetics; D014122:Toxoplasma / Q000254:growth & development / Q000276:immunology / Q000472:pathogenicity; D014124:Toxoplasmosis, Animal / Q000235:genetics / Q000276:immunology* / Q000473:pathology* / Q000628:therapy
chemical_list: D000911:Antibodies, Monoclonal; D018949:Antigens, CD1; D055610:Antigens, CD1d; D000953:Antigens, Protozoan; D015704:CD4 Antigens; D016693:Receptors, Antigen, T-Cell, alpha-beta