Molecular mechanisms of T helper 1 and T helper 2 cell development: differential signalling in response to Interleukin-12

Passini, Nadia (1999). Molecular mechanisms of T helper 1 and T helper 2 cell development: differential signalling in response to Interleukin-12. PhD thesis The Open University.



Interleukin-12, a heterodimeric cytokine produced by activated monocytes and dendritic cells, plays a crucial role in regulating IFN-ү production and in the generation of IFN-ү producing T helper 1 cells. Here is shown that the IL-12Rß2 subunit, a recently cloned binding and signal transducing component of the IL- 12R, is expressed on human Thl but not Th2 clones, and is induced during differentiation of human naive T cells along the Thl but not the Th2 pathway. IL- 12 and IFN-a but not IFN-ү induce expression of the IL-12Rß2 chain during in vitro T cell differentiation following antigen receptor triggering, whereas IL-4 inhibits IL-12Rß2 transcription. Conversely, IFN-ү but not IFN-ɑ can rescue IL-12Rß2 mRNA expression and restore IL-12 responsiveness in early developing mouse Th2 cells. IFN-ɑ activity in humans is mediated by Stat4.
The DNase Hypersensitive Site analysis allowed the characterisation of chromatin structure and accessibility of the IL-12Rß2 locus. Naive T cells as well as Th2 cells show a relative “closed” chromatin configuration, whereas Thl cells displayed an accessible chromatin configuration with a complex pattern of DNase Hypersensitivity. The characterisation of the DH sites selectively present in Thl cells allowed the identification of: i) a TATA-less, CpG rich, IL-12Rß2 minimal promoter ii) IL-12 and IFN-ɑ responsive enhancer regions. These regions contain GAS binding sites that not only bind Stat4, but also that are transcriptionally active. These data provide strong evidence that Stat4 plays a key role in the regulation of the Thl-specific expression of IL-12Rß2. Furthermore, the IL-12RP2 GAS. sites display a binding selectivity and do not efficiently bind Stat1. Thus, the week effects exerted by IFN-ү in humans on IL-12Rß2 gene regulation, and the consequent failure to induce Thl development, can be explained by the inefficient binding of the IFN-ү-induced Stat1 to the IL-12Rß2 GAS sites.

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