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

D E Jones, L U Buxbaum, P Scott
Journal of Immunology 2000 July 1, 165 (1): 364-72
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 beta2 (IL-12Rbeta2) mRNA expression by CD4+ T cells. Furthermore, decreased IL-12Rbeta2 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-12Rbeta2 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-12Rbeta2 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 may be dictated by the pathogen, rather than the host.

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