Roles for NK Cells and an NK Cell-Independent Source of Intestinal Gamma Interferon for Innate Immunity toCryptosporidium parvumInfection

Abstract

A gamma interferon (IFN-γ)-dependent innate immune response operates against the intestinal parasiteCryptosporidium parvumin T- and B-cell-deficient SCID mice. Although NK cells are a major source of IFN-γ in innate immunity, their protective role againstC. parvumhas been unclear. The role of NK cells in innate immunity was investigated using Rag2^−/−mice, which lack T and B cells, and Rag2^−/−γ_c^−/−mice, which, in addition, lack NK cells. Adult mice of both knockout lines developed progressive chronic infections; however, on most days the level of oocyst excretion was higher in Rag2^−/−γ_c^−/−mice and these animals developed morbidity and died, whereas within the same period the Rag2^−/−mice appeared healthy. Neonatal mice of both mouse lines survived a rapid onset of infection that reached a higher intensity in Rag2^−/−γ_c^−/−mice. Significantly, similar levels of intestinal IFN-γ mRNA were expressed in Rag2^−/−and Rag2^−/−γ_c^−/−mice. Also, infections in each mouse line were exacerbated by treatment with anti-IFN-γ neutralizing antibodies. These results support a protective role for NK cells and IFN-γ in innate immunity againstC. parvum. In addition, the study implies that an intestinal cell type other than NK cells may be an important source of IFN-γ during infection and that NK cells may have an IFN-γ-independent protective role.