Role of interleukin-12 and interleukin-18 in murine immune cell regulation

Interleukin 12 plays a central role in NK cell activation and CD4 +T cell differentiation. IL-12 acts via a receptor composed of IL-12Rβ1 and IL-12Rβ2 subunits. IL-12Rβ1 plays a primary role in ligand binding whereas IL-12Rβ2 is responsible for signaling. IL-18 shares some functional activities of IL-12. However, there is a considerable amount of contradictory data in the literature regarding the requirements for IL-12 and IL-18 responsiveness.; This work examined the expression of IL-12Rβ2 on murine NK and T cells and the requirements for acquisition of IL-12/IL-18 responsiveness. NK cells stimulated with IL-2+IL-12 or IL-2+IL-18 exhibited rapid upregulation of IFN-γ expression followed by upregulation of IL-10 or IL-13 mRNA, respectively. NK cells from IL-12Rβ2-deficient mice responded to IL-2+IL-18 independently of IL-12. Furthermore, flow cytometric analyses revealed that NK cells activated in vitro with IL-2 differentiate into two distinct cell subsets expressing different levels of IL-12Rβ2.; Like NK cells, NK-T cells also responded to IL-2+IL-12 or IL-2+IL-18 without stimulation of the antigen-specific T cell receptor (TCR). Previously, it was thought that all T cells require activation via the TCR in order to respond to IL-12 or IL-18. Thus, responsiveness of conventional T cells to IL-2+IL-12 or IL-2+IL-18 in the absence of TCR ligation was assessed. Naïve CD4+T cells from wild type or DO11.10/Rag2−/− OVA-specific TCR transgenic mice responded to IL-2+IL-12 or IL-2+IL-18 by expressing IFN-γ and cells grown in IL-2+IL-12 exhibited signs of polarization towards a T_H1 phenotype.; Transgenic BALB/c mice constitutively expressing the IL-12Rβ2 chain were generated and the role of the IL-12Rβ2 in T_H2 phenotype development was analyzed using the T_H1-dependent murine leishmaniasis model. Despite constitutive expression of the IL-12Rβ2 chain, transgenic T_H2 cells did not revert to T_H1 when restimulated with IL-12 and mice remained susceptible to Leishmania. The role of IL-12Rβ2 in T_H1 cell development was also analyzed using the same model. Resistant C57BL/6 mice defective in IL-12Rβ2 gene exhibited susceptibility to L. major infection and expressed a T _H2 phenotype, consistent with a critical role for IL-12 in this model.; Thus understanding the expression of IL-12Rβ2 in NK and CD4 +T cells and its regulation by cytokines may constitute an important element in studies in cancer and autoimmune disease therapy.