Type I IFNs promote the early IFN-gamma response and the IL-10 response in Leishmania mexicana infection.
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/betaR-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/betaR-deficient vs. wild-type mice. IFN-alpha/betaR-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/betaR-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.
Buxbaum
L U
LU
VA Medical Center, Philadelphia, PA 19104-6073, USA. buxbaum@mail.med.upenn.edu
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000737:chemistry / Q000276:immunology; D007370:Interferon Type I / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis*; D016753:Interleukin-10 / Q000096:biosynthesis*; D018664:Interleukin-12 / Q000097:blood; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis; D007894:Leishmania mexicana / Q000276:immunology*; D016773:Leishmaniasis, Cutaneous / Q000276:immunology*; D008198:Lymph Nodes / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D053633:Receptor, Interferon alpha-beta / Q000172:deficiency
D007370:Interferon Type I; D053645:Interleukin-2 Receptor alpha Subunit; D016753:Interleukin-10; D053633:Receptor, Interferon alpha-beta; D018664:Interleukin-12; D007371:Interferon-gamma