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Experimental African Trypanosomiasis: A Subset of Pathogenic, IFN--Producing, MHC Class II-Restricted CD4⁺ T Cells Mediates Early Mortality in Highly Susceptible Mice¹

Department of Veterinary Microbiology, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, Canada

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- dependent. In this study we show that IFN- is produced predominantly by CD3⁺Thy1.2⁺TCR⁺CD4⁺ T cells shortly before the death of infected mice. Mortality may therefore be dependent on IFN--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- 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- 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-. IFN-, 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.

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