Resistance to the African trypanosomes is IFN-gamma dependent

The role of variant surface glycoprotein (VSG)-specific Th cell responses i n determining resistance to the African trypanosomes was examined by compar ing Th cell responses in relatively resistant and susceptible mice as well as in cytokine gene knockout mice infected with Trypanosoma brucei rhodesie nse. Resistant B10.BR and C57BL/6 mice expressed Th1 cell cytokine response s to VSG stimulation during infection, while susceptible C3H mice produced weak or no Th1 cell cytokine responses. Neither resistant B10.BR and C57BL/ 6 mice nor susceptible C3H mice made detectable Th2 cell cytokine responses to parasite Ag, To more closely examine the potential role of IFN-gamma an d other cytokines in host resistance, we determined the resistance phenotyp es and Th cell responses of IFN-gamma and IL-4 knockout mice. Infected C57B L/6-IFN-gamma knockout mice were as susceptible as C57BL/6-scid mice and ma de an IL-2, but not an IL-4, cytokine response to VSG, while C57BL/6-IL-4 k nockout mice were as resistant as the wild-type strain and exhibited both I L-2 and IFN-gamma cytokine responses. Passive transfer of spleen cells from wild-type mice to IFN-gamma knockout mice resulted in enhanced survival. B oth wild-type and IFN-gamma knockout mice controlled parasitemia with VSG-s pecific Ab responses, although parasitemias were higher in the IFN-gamma kn ockout mice. Overall, this study demonstrates for the first time that relat ive resistance to African trypanosomes is associated with a strong Th1 cell response to parasite Ags, that IFN-gamma, but not IL-4, is linked to host resistance, and that susceptible animals do not make compensatory Th2 cell responses in the absence of Th1 cell cytokine responses.