Interleukin 12 induces stable priming for interferon gamma (IFN-gamma) production during differentiation of human T helper (Th) cells and transient IFN-gamma production in established Th2 cell clones.

Abstract

SummaryInterleukin 12 facilitates the generation of a T helper type 1 (Thl) response, with high interferon 3' (IFN-3') production, while inhibiting the generation of IL-4-producing Th2 calls in polyclonal cultures of both human and murine T cells and in vivo in the mouse. In this study, we analyzed the effect of IL-12, present during cloning of human T cells, on the cytokine profile of the clones. The culture system used allows growth of clones from virtually every T cell, and thus excludes the possibility that selection of precommitted Th cell precursors plays a role in determining characteristics of the clones. IL-12 present during the cloning procedures endowed both CD4 + and CD8 + clones with the ability to produce IFN-3" at levels severalfold higher than those observed in clones generated in the absence of IL-12. This priming was stable because the high levels of IFN-3' production were maintained when the clones were cultured in the absence of IL-12 for 11 d. The CD4 + and some of the CD8 + clones produced variable amounts of IL-4. Unlike IFN-3', IL-4 production was not significantly different in clones generated in the presence or absence of IL-12. These data suggest that IL-12 primes the done progenitors, inducing their differentiation to high IFN-3'-producing clones. The suppression of IL-4-producing cells observed in polyclonally generated T cells in vivo and in vitro in the presence of IL-12 is not observed in this donal model, suggesting that the suppression depends more on positive selection of non-IL-4-producing cells than on differentiation of individual clones. However, antigen-specific established Th2 clones that were unable to produce IFN-3, with any other inducer did produce IFN-3" at low but significant levels when stimulated with IL-12 in combination with specific antigen or insoluble anti-CD3 antibodies. This induction of IFN-3' gene expression was transient, because culture of the established clones with IL-12 for up to 1 wk did not convert them into IFN-3" producers when stimulated in the absence of IL-12. These results suggest that Th clones respond to IL-12 treatment either with a stable priming for IFN-3' production or with only a transient low level expression of the IFN-3" gene, depending on their stage of differentiation. ecent work from our and other laboratories (1-5) has shown that human CD4 + Th cell clones, in analogy to the murine system (6, 7), can be subdivided into at least three distinct functional subsets based on their cytokine secretion profile. One type of CD4 § done (Thl) produces IL-2, IFN-3`, and TNF-j3, but not IL-4 or IL-5; a second type (Th2) produces IL-4 and IL-5, but not IL-2, IFN-3`, or TNF-B; R. Manetti and F. Gerosa contributed equally to this work. and a third type (Th0) produces both Thl-and Th2-type cytokines (1,3,5,6). Although most CD8 + human T cell dones exhibit a Thl-like cytokine profile (3, 5), some CD8 + clones showing a Th2-1ike phenotype have also been described (s, 9).Several factors can affect the development of Thl or Th2 responses both in v...

Surface Expression of the IFN-γR2 Chain Is Regulated by Intracellular Trafficking in Human T Lymphocytes

“…This would appear to be a mechanism for their stable commitment to the Th2 phenotype (37). In contrast, established human Th2 clones can still be induced by IL-12 to produce IFN-␥ (40). Our data indicate that in humans down-regulation of surface IFN-␥R2 is mainly involved in the prevention of IFN-␥-mediated apoptosis by T cells rather than an event intrinsically linked to the polarization of cells to the Th1 lineage (41).…”

Regression of mouse tumours and inhibition of metastases following administration of a Semliki Forest virus vector with enhanced expression of IL-12

“…In addition, a further antitumour activity of IL-12 is its ability to induce IFN-g production by T cells, which in turn mediates antiangiogenic effects. [23][24][25] Previous studies have shown that the amount of IL-12 available at the tumour site is critical for tumour regression, since it determines the number and type of infiltrating leucocytes. 21 It may also mediate the antiangiogenic effect of IL-12, 18 although the relative contribution of these two effects to the antitumour activity of IL-12 is not clear.…”

“…IL-12 induces the differentiation of T-helper1 (Th1) CD4+ cells, which are inducers of IFN-g production. 23 It has been reported that tumour treatment using IL-12 is associated with the expression of the cytokine IFN-g and chemokines such as IP-10 at the tumour site, inducing the antitumour effect through a direct toxic effect on the tumour cells or by activating potent antiangiogenic mechanisms. 24 The induced antiangiogenic mechanisms are complex and dependent both on the direct effect of the proinflammatory cytokines/chemokines on endothelial cells and the recruitment of effector NK and T-cells.…”

La respuesta celular inmune en la leishmaniasis cutánea americana

“…Por tanto, se ha estudiado la posibilidad de tratar la leishmaniasis con compuestos potenciadores de la respuesta inmune, proceso conocido El conocimiento del estado inmunológico de los pacientes con leishmaniasis puede ser una gran herramienta para lograr un tratamiento efectivo de las formas clínicas crónicas de difícil resolución con antimoniales pentavalentes. Por ejemplo, en algunos estudios con modelos experimentales en los que se utilizó IL-12, se ha observado que esta citocina tiene un papel importante en la iniciación o establecimiento de una respuesta T h l protectora con alta producción de lFNy que, a su vez, inhibe la generación de una respuesta Th2 (50,63). En los ratones susceptibles, la inmunoterapia con IL-12 durante las primeras semanas de infección previene el desarrollo de una respuesta tipo Th2 y promueve el desarrollo de una respuesta tipo Thl dependiente de lFNy que conlleva a la cura de las lesiones (49).…”