IL-4 Protects Adult C57BL/6 Mice from Prolonged Cryptosporidium parvum Infection: Analysis of CD4+αβ+IFN-γ+ and CD4+αβ+IL-4+ Lymphocytes in Gut-Associated Lymphoid Tissue During Resolution of Infection

Abstract

Resistance of adult C57BL/6 mice to severe Cryptosporidium parvum infection is dependent on CD4+αβ+ TCR lymphocytes. In this study, we demonstrated that treatment with anti-IFN-γ mAb extended oocyst excretion 18 days longer, and anti-IL-4 mAb extended oocyst excretion at least 11 days longer than isotype control mAb treatment. Analysis of the specific activity of anti-IFN-γ mAb present in treated mouse sera suggested that IFN-γ may have a limited role in the resolution phase of infection. Changes were also documented in numbers of CD4+αβ+IFN-γ+ and CD4+αβ+IL-4+ lymphocytes in Peyer’s patches and intraepithelium of adult C57BL/6 mice during resolution of C. parvum infection. Resistance to initial severe infection was associated with CD4+αβ+IFN-γ+ lymphocytes, and eventual resolution of infection was associated with CD4+αβ+IL-4+ lymphocytes. Analysis of cytokine expression following in vitro stimulation with C. parvum Ags during resolution of infection demonstrated consistent increases in CD4+αβ+IL-4+ lymphocytes, but not CD4+αβ+IFN-γ+ lymphocytes. The relevance of CD4+αβ+IL-4+ lymphocytes in protection against C. parvum was then evaluated in C57BL/6 IL-4 gene knockout mice (IL-4−/−). Adult IL-4−/− mice excreted oocysts in feces approximately 23 days longer than IL-4+/+ mice. Further, anti-IFN-γ mAb treatment increased the severity and the duration of infection in IL-4−/− mice compared with those in IL-4+/+ mice. Together, the data demonstrated that IFN-γ was important in the control of severity of infection, and either IFN-γ or IL-4 accelerated termination of infection. However, neither IL-4 nor IFN-γ was required for the final clearance of infection from the intestinal tract of adult mice.