Impaired immunity and altered pulmonary responses in mice with a disrupted interferon-gamma receptor gene exposed to the irradiated Schistosoma mansoni vaccine

Abstract

A high level of protection against Schistosoma mansoni is elicited in mice by the irradiated cercaria vaccine and interferon-gamma (IFN-gamma) is a key cytokine in the pulmonary effector response. The role of this cytokine has been investigated in mice with a targeted disruption of the IFN-gamma receptor gene (IFN-gamma R-/- mice). The level of protection was impaired relative to that elicited in C57BL/6 and 129 wild-type (WT) animals. These two groups developed compact effector foci, of largely mononuclear cell composition, around individual challenge parasites migrating through the lungs. In contrast the IFN-gamma R-/- mice showed a massive and generalized leucocytic infiltration of the airways and interstitium in which eosinophils were a prominent feature. Cultures of airway leucocytes from C57BL/6 mice produced abundant IFN-gamma whilst those from IFN-gamma R-/- mice produced interleukin-4 (IL-4), IL-5 and IL-10, indicating default to the Th2 pathway; the WT animals showed an intermediate response. The pattern of cytokine gene transcripts in whole lung tissue agreed remarkably well with the level of cytokine protein detected in leucocyte cultures, with the exception of substantial IL-4 mRNA but negligible protein in C57BL/6 mice. The loose but intense infiltrate of leucocytes in the lungs of IFN-gamma R-/- mice was clearly ineffective in eliminating challenge parasites, whereas the level of IFN-gamma protein and mRNA in the lungs of C57BL/6 and WT mice correlated with the size and compactness of effector foci. On the basis of these and earlier observations, we suggest that a primary role for IFN-gamma is to promote intercellular adhesion between the leucocytes in an effector focus, promoting its ability to block parasite migration.