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

• Published in: The Journal of immunology (1950) 1999-11, Vol.163 (10), p.5257-5264
• Main Authors: Thibodeaux, D K, Hunter, S E, Waldburger, K E, Bliss, J L, Trepicchio, W L, Sypek, J P, Dunussi-Joannopoulos, K, Goldman, S J, Leonard, J P
• Format: Article
• Language: English
• Subjects: AB7 antigen; Animals; Antibodies, Blocking - pharmacology; Antigen-Presenting Cells - immunology; Autocrine Communication - immunology; B7-1 Antigen - immunology; Female; g-Interferon; Injections, Subcutaneous; Interferon-gamma - deficiency; Interferon-gamma - genetics; Interferon-gamma - secretion; Interleukin 12 receptors; Interleukin-12 - administration & dosage; Interleukin-12 - genetics; Interleukin-12 - metabolism; Killer Cells, Natural - immunology; Killer Cells, Natural - secretion; Lymph Nodes - cytology; Lymph Nodes - immunology; Lymph Nodes - secretion; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Knockout; Receptors, Interleukin - biosynthesis; Receptors, Interleukin - genetics; Receptors, Interleukin-12; Recombinant Proteins - administration & dosage; T-Lymphocytes - immunology; T-Lymphocytes - secretion
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.163.10.5257

The biological response to IL-12 is mediated through specific binding to a high affinity receptor complex composed of at least two subunits (designated IL-12Rbeta1 and IL-12Rbeta2) that are expressed on NK cells and activated T cells. The selective loss of IL-12Rbeta2 expression during Th2 T cell differentiation suggests that regulation of this receptor component may govern IL-12 responsiveness. In murine assays, down-regulation of IL-12Rbeta2 expression can be prevented by treatment with IFN-gamma, indicating that 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-12Rbeta1 and beta2 mRNA is increased in the lymph nodes of naive mice following systemic administration of murine rIL-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 regulation was independent of secondary IFN-gamma secretion. Data from fractionated lymph node cells as well as rmIL-12-treated B cell-deficient mice suggest that IL-12-responsive B cells may represent an alternative cellular source for IFN-gamma production. However, the strength of the biological response to rmIL-12 is not governed solely by receptor expression, as rmIL-12-induced IFN-gamma secretion from cultured lymph node cells is accessory cell dependent and can be partially blocked by inhibition of B7 costimulation.