Mice with STAT6-targeted gene disruption develop a Th1 response and control cutaneous leishmaniasis

Abstract

The cutaneous growth of Leishmania mexicana was measured in STAT6-deficient mice (STAT6-/-) and compared with that in similarly infected wild-type (STAT6+/+) mice. Following s.c. inoculation with 5 x 10(6) amastigotes of L. mexicana into the shaven rump, STAT6+/+ mice developed large, nonhealing cutaneous lesions, while STAT6-/- mice failed to develop detectable lesions during most of the course of study. As infection progressed, STAT6+/+ mice infected with L. mexicana displayed significantly higher titers of Leishmania-specific IgG1 and IgE compared with STAT6-/- mice, which conversely produced significantly higher titers of Leishmania-specific IgG2a, indicating development of a Th1-like response in the latter group. At 12 wk postinfection, Leishmania Ag-stimulated lymph node cells from STAT6-/- mice produced significantly higher amounts of IL-12 and IFN-gamma than those from STAT6+/+ mice as measured by ELISA. However, there was no significant difference in IL-4 production between the two groups. Semiquantitative RT-PCR of transcript levels in intact draining lymph nodes and skin from inoculation sites confirmed a similar pattern of cytokines in vivo as that observed in stimulated lymph node cells in vitro. These results indicate that STAT6-mediated IL-4 signaling is critical for progression of L. mexicana infection in genetically susceptible mice and demonstrate that in the absence of STAT6, susceptible mice default toward a Th1-like response and control cutaneous L. mexicana infection.