IL-4-independent inhibition of IL-12 responsiveness during Leishmania amazonensis infection

Leishmania amazonensis induces a nonhealing infection in C3H mice, whereas infection with Leishmania major is self-healing, We found that C3H mice infected with L, amazonensis exhibited decreased IL-12 production, which could account for the susceptibility to this organism, However, exogenous IL-12 administration failed to induce a healing immune response, The failure of L, amazonensis-infected C3H mice to respond to IL-12 was associated with a specific defect in IL-12 receptor beta 2 (IL-12R beta 2) mRNA expression by CD4(+) T cells, Furthermore, decreased IL-12R beta 2 mRNA expression correlated with a decrease in the IL-12-signaling capacity of the lymph node (LN) cells. IL-4 did not contribute to susceptibility or down-regulation of the IL-12R beta 2 subunit, because IL-4(-/-) mice remained susceptible to L. amazonensis infection, even after IL-12 administration, and CD4(+) cells from infected IL-4(-/-) mice also had reduced expression of IL-12R beta 2 mRNA. These results demonstrate that regulation of the IL-12 receptor, independent of IL-4, is a point of control for the immune response to leishmaniasis. In contrast to experimental L. major infections, where host genetics control susceptibility, these studies demonstrate that the lack of IL-12 responsiveness mag be dictated by the pathogen, rather than the host.