T cell responses during murine schistosomiasis mansoni

This thesis examines the development of CD4+ and CD8 + responses in C57BL/6 WT and IL-4-/- mice during infection with Schistosoma mansoni. In WT mice, acute schistosomiasis is characterized by strong simultaneous CD4+ Th2-like and type 1-like CD8+ responses. This was determined by examining the cytokine profile of purified splenic T cell populations upon TCR cross-linking. The CD8+ cells were in part schistosome antigen-specific, and T cell help could come from either IL-2 or IL-4. Analysis of T cell responses during schistosomiasis revealed that the CD8+ cell response was first induced in the prepatent phase, amplified in acute phase and maintained through to the chronic stage. Maintenance of a chronic phase CD8+ response requires living worms, because treating the mice with an anti-helminthic drug during acute infection reduced the strength CD8+ responses compared to those in untreated, chronically infected mice. Infection with single sex schistosomes was also able to induce CD8+ cells, which is consistent with the presence of activated CD8+ cells prior to the onset of egg production. IFN-gamma production upon TCR cross-linking by CD8+ cells was largely IL-4-dependent for acute phase cultures. IL-2 and IL-4 depletion experiments with prepatent and chronic stage cells suggested increased dependence on IL-2 for IFN-gamma production compared to acute phase cultures. This may reflect the kinetics of the CD4+ response, since CD4+ cells are weakly Th0 in the prepatent phase, became strongly Th2-like in the acute phase, and return to a more Th0-like phenotype in the chronic phase.;The absence of IL-4 during acute schistosomiasis is lethal for B6 mice. Acute phase CD4+ cells from IL-4-/- mice were qualitatively Th1-like, but severely impaired in function, producing less IFN-gamma than the strongly Th2-like WT CD4+ cells. They also proliferated less well than WT cells, without producing less IL-2. Schistosome-induced CD8+ cell responses were strongly defective in IL-4-/- mice as well. CD8+ cells from these animals produced decreased IFN-gamma levels but had similar levels of IL-2 and proliferation indexes to WT cells. The results suggest that IL-4 may be more important to the generation of strong CD8+ cell responses in vivo than previously appreciated.