IL-12-Deficient Mice Are Defective in IFNγ Production and Type 1 Cytokine Responses

Abstract

IL-12 is a cytokine that can exert regulatory effects on T and NK cells and promote Th1 responses. To delineate further the physiologic role of IL-12 in immunity, mice deficient for this cytokine were generated. IL-12-deficient mice were impaired but not completely lacking in the ability to produce IFN gamma following endotoxin administration and to mount a Th1 response in vivo, as measured by antigen-induced IFN gamma secretion by immune lymph node cells in vitro. In contrast, secretion of IL-4 was enhanced, while proliferation and secretion of IL-2 and IL-10 were normal following antigen stimulation. DTH responses were significantly reduced in IL-12-deficient mice, but no defect in allogeneic CTL responses was observed. These results indicate that IL-12 plays an essential role in regulating IFN gamma production and in facilitating normal DTH responses. However, other phenomena associated with Th1 responses and cell-mediated immunity, i.e., IL-2 secretion and CTL generation, were not compromised in the absence of IL-12.

Cutting Edge: Type I IFNs Provide a Third Signal to CD8 T Cells to Stimulate Clonal Expansion and Differentiation

“…A similar requirement has been demonstrated in vivo (9), and the "third signal" acts as a switch that determines whether exposure to Ag results in tolerance vs full activation and development of memory (10,11). IL-12 cannot be the only source of signal 3 since CTL responses can occur in IL-12-deficient mice (9,12). As shown in this study, type I IFN can also provide the third signal for clonal expansion and differentiation of naive CD8 T cells and does so by acting directly on the T cell.…”

Small interference RNA modulation of IL‐10 in human monocyte‐derived dendritic cells enhances the Th1 response

“…CD40 and CD40L interactions play important roles in the priming, differentiation and effector function of helper and cytotoxic T cells [23]. IL-12 is an inducible cytokine composed of 35-and 40-kDa subunits and is crucial to promoting the development of Th1 cells and cell-mediated immunity [24][25][26]. DC are major IL-12 producers [27,28], and IL-12 production after cognate interaction with CD4 + T cells is largely dependent on CD40/CD40L interaction [29].…”

The biology of Stat4 and Stat6

“…This has been clearly demonstrated in mice de®cient for the cytokines themselves or their receptor subunits. For example, mice de®cient for IL-12 or IL-12Rb1 chain are unable to generate Th1 cells, and mice lacking IL-4 or the IL-4Ra chain are de®cient for Th2 responses (Kopf et al, 1993;Kuhn et al, 1991;Magram et al, 1996;Noben-Trauth et al, 1997;Wu et al, 1997).…”