Autocrine regulation of IL-12 receptor expression is independent of secondary IFN-gamma secretion and not restricted to T and NK cells

The biological response to IL-12 is mediated through specific binding to a high affinity receptor complex composed of at least two subunits (designate d IL-12R beta 1 and IL-12R beta 2) that are expressed on NK cells and activ ated T cells, The selective loss of IL-12R beta 2 expression during Th2 T c ell differentiation suggests that regulation of this receptor component may govern IL-12 responsiveness. In murine assays, down-regulation of IL-12R b eta 2 expression can be prevented by treatment with IFN-gamma, indicating t hat receptor expression and hence IL-12 responsiveness may be regulated, at least in part, by the local cytokine milieu. In this study, we report that cellular expression of both IL-12R beta 1 and beta 2 mRNA is increased in the lymph nodes of naive mice following systemic administration of murine r IL-12 (rmIL-12). Changes in IL-12R mRNA were associated with increased IFN- gamma secretion following ex vivo activation of lymph node cells with rmIL- 12, indicating the presence of a functional receptor complex. Expression of IL-12R mRNA was not restricted to lymph node T cells, and its autocrine re gulation was independent of secondary IFN-gamma secretion. Data from fracti onated lymph node cells as well as rmIL-12-treated B cell-deficient mice su ggest that IL-12-responsive B cells may represent an alternative cellular s ource for IFN-gamma production. However, the strength of the biological res ponse to rmIL-12 is not governed solely by receptor expression, as rmIL-12- induced IFN-gamma secretion from cultured lymph node cells is accessory cel l dependent and can be partially blocked by inhibition of B7 costimulation.