Regulation of interleukin-12 signalling during T helper phenotype development - PubMed (original) (raw)

Review

Regulation of interleukin-12 signalling during T helper phenotype development

N G Jacobson et al. Adv Exp Med Biol. 1996.

Abstract

The experiments described above have allowed us to define the molecular events in IL-12 signalling. Within minutes after IL-12 treatment of responsive cells, Stat1, Stat3, and Stat4 are tyrosine phosphorylated. These molecules form nuclear DNA-binding complexes consisting of homodimeric Stat1 and heterodimeric Stat3-Stat4 complexes. In a murine in vitro phenotype development model, T cells rapidly and selectively lose their capacity to respond to IL-12 upon acquisition of the Th2 phenotype. This hyporesponsiveness is manifested by the inability of IL-12 to induce IFN gamma production in differentiated Th2 cells, as well as the inability of IL-12 to induce the activation of Stat4. Despite the functional defect of IL-12 signalling in Th2 cells, all known components of the IL-12 signal transduction pathway are present. We speculate that in Th2 cells, the second receptor chain may be absent or one of the other components may be modified. Genetic experiments in Balb/c and B10.D2 strains of mice have demonstrated several differences in T helper differentiation in vitro. Stimulation of T cells under neutral conditions results in a bias of Balb/c T cells toward the Th2 extreme and B10 T cells toward the Th1 extreme of cytokine production. Following stimulation under neutral conditions, B10 T cells retain the ability to respond to IL-12 while Balb/c T cells lose IL-12 responsiveness. Mating experiments have demonstrated that the B10 genetic effect is dominant in F1 mice. Analysis of backcrossed animals has suggested that the ability to respond to IL-12 in the secondary stimulation may be controlled by a single dominant B10 gene. The results we describe may have profound implications for allergy. Since allergic responses are largely due to the activation of the Th2 subset of T lymphocytes, a better understanding of T cell phenotype development may reveal multiple targets for therapeutic intervention. First, a better understanding of Th1 phenotype induction in response to IL-12 may allow prevention of in vivo allergic responses using pharmacological tools which bias allergen-specific responses to the Th1 subset. Second, a molecular explantation of why Th2 cells fail to reverse phenotype in response to IL-12 may allow treatment of atopic individuals to remove the disease-promoting T lymphocyte compartment. Finally, a better understanding of the basis for genetic differences in murine T helper cell differentiation may allow us to identify a causative genetic element in humans, yielding better diagnostic and therapeutic methods.

PubMed Disclaimer

Publication types

MeSH terms

Substances

LinkOut - more resources