title: Experimental African trypanosomiasis: a subset of pathogenic, IFN-gamma-producing, MHC class II-restricted CD4+ T cells mediates early mortality in highly susceptible mice.
abstract: Infections of highly susceptible BALB/c mice with virulent strains of Trypanosoma congolense or Trypanosoma brucei result in rapid death (8 days). We have previously shown that this mortality is IFN-gamma dependent. In this study we show that IFN-gamma is produced predominantly by CD3+Thy1.2+TCRbeta+CD4+ T cells shortly before the death of infected mice. Mortality may therefore be dependent on IFN-gamma-producing CD4+ T cells. Surprisingly, infected CD4+/+ and CD4-/- BALB/c mice have similar parasitemia and survival time. In infected CD4-/- mice, the production of both IFN-gamma and IL-10 is very low, suggesting that both cytokines are predominantly produced by CD4+ T cells and that the outcome of the disease might depend on the balance of their effects. Infected BALB/c mice partially depleted of CD4+ T cells or MHC class II function have lower parasitemia and survive significantly longer than infected normal BALB/c mice or infected BALB/c mice whose CD4+ T cells are fully depleted. Partial depletion of CD4+ T cells markedly reduces IFN-gamma secretion without a major effect on the production of IL-10 and parasite-specific IgG2a Abs. Based on our previous and current data, we conclude that a subset of a pathogenic, MHC class II-restricted CD4+ T cells (Tp cells), activated during the course of T. congolense infection, mediates early mortality in infected BALB/c mice via excessive synthesis of IFN-gamma. IFN-gamma, in turn, exerts its pathological effect by enhancing the cytokine release syndrome of the macrophage system activated by the phagocytosis of parasites. We speculate that IL-10-producing CD4+ T cells might counteract this effect.
authors.affiliation: Department of Veterinary Microbiology, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, Canada.
authors.forename: Meiqing
authors.initials: M
authors.lastname: Shi
authors.forename: Guojian
authors.initials: G
authors.lastname: Wei
authors.forename: Wanling
authors.initials: W
authors.lastname: Pan
authors.forename: Henry
authors.initials: H
authors.lastname: Tabel
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal; D017252:CD3 Complex / Q000378:metabolism; D015704:CD4 Antigens / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D016827:CD8 Antigens / Q000235:genetics; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005260:Female; D020022:Genetic Predisposition to Disease; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis*; D016753:Interleukin-10 / Q000096:biosynthesis; D018664:Interleukin-12 / Q000097:blood; D053762:Interleukin-12 Subunit p40; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D021122:Protein Subunits / Q000097:blood; D051381:Rats; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D014348:Trypanosoma congolense / Q000276:immunology; D014353:Trypanosomiasis, African / Q000235:genetics / Q000276:immunology* / Q000401:mortality
chemical_list: D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D015704:CD4 Antigens; D016827:CD8 Antigens; D018984:Epitopes, T-Lymphocyte; D000949:Histocompatibility Antigens Class II; D053762:Interleukin-12 Subunit p40; D021122:Protein Subunits; D011948:Receptors, Antigen, T-Cell; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma