Type I IFNs promote the early IFN-γ response and the IL-10 response in Leishmania mexicana infection

P>The protozoan parasite Leishmania mexicana causes chronic cutaneous disease in humans and most mouse strains. We previously showed that STAT4-deficient mice, but not IL-12p40-deficient mice, have more parasites and progressively growing lesions unlike those of wild-type mice, the lesions and parasite burdens of which plateau by 10-12 weeks post-infection. This demonstrates a STAT4-dependent, IL-12/IL-23-independent pathway of parasite control. Type I IFNs are important in viral and other infections and can activate STAT4. We found that IFN-alpha/beta R-deficient mice have a nonpersistent, early IFN-gamma defect, and a persistent, early IL-10 defect, without changes in serum IL-12 or LN-derived nitric oxide. We found less IL-10 per cell in CD25+CD4+ T cells and possibly fewer IL-10-producing cells in the draining LN of IFN-alpha/beta R-deficient vs. wild-type mice. IFN-alpha/beta R-deficient mice have chronic, nonprogressive disease, like wild-type mice, suggesting that IL-10 and IFN-gamma defects may balance each other. Our data indicate that although type I IFNs help promote early Th1 responses, they are not the missing activators of STAT4 responsible for partial control of L. mexicana. Also, the lack of lesion resolution in IFN-alpha/beta R-deficient mice despite lower IL-10 levels indicates that other pathways independent of T cell IL-10 help prevent an IL-12-driven clearance of parasites.