TNF is essential for the cell-mediated protective immunity induced by the radiation-attenuated schistosome vaccine

C57BL/6 mice exposed to the radiation-attenuated schistosome vaccine exhibi t high levels of protective immunity. The cell-mediated pulmonary effector mechanism involves IFN-gamma-producing CD4(+) T cells in a focal response a round challenge larvae. IFN-gamma can promote production of TNF and can syn ergize with this cytokine in its actions on responder cells, We have examin ed whether TNF plays a role in lung phase immunity to schistosomes using mi ce with a disrupted gene for TNFRI (TNFRI-/-). The most dramatic finding wa s that the schistosome vaccine elicited no protection whatsoever in these m ice. However, this could not be attributed to a lack of responder cells, be cause more lymphocytes were lavaged from the airways of TNFRI-/- than wild- type mice. Furthermore, CD4(+) T cells were equally represented in airway p opulations from the two groups and produced IFN-gamma upon Ag stimulation i n vitro. In contrast, pulmonary macrophage function was defective in TNFRI- /- mice, as indicated by a failure to up-regulate inducible NO synthase mRN A. Histopathological analysis revealed that focal infiltrates were of simil ar size and cell composition in the two groups but that more parasites were free of foci in the TNFRI-/- mice. These animals had a greatly impaired Ig G response to schistosomes, which may explain their lack of residual protec tion due to Ab in a situation where cell-mediated immunity is disabled. We suggest that the absence of protective immunity could result from a retarde d build-up of leukocytes around migrating lung worms and/or a deficit in ac cessory cell function within a focus, both of which would permit parasite e scape.