Interleukin-12 signalling pathways in human T lymphocytes

The aim of the work that constitutes the present PhD thesis was to elucidate the intracellular signalling pathways downstream of the cytokine Interleukin-12 (IL-12) in human T lymphocytes. IL-12 plays a key role in the onset of the cellular immune response by driving the differentiation of naive Th cells into Th1 cells. The important role of IL-12 in human immune responses has been emphasised by recent reports that mutations of the IL-12 receptor (IL-12R) are found in immunodeficient patients suffering from recurrent Mycoplasma sp. and Salmonella sp. infections. IL-12 exerts its function through interaction with the IL-12R that leads to the activation of the Janus kinases Tyk2 and Jak2. IL-12 also induces tyrosine phosphorylation and DNA binding of STAT4 (Signal Transducer and Activator of Transcription 4), an essential response for Th1 cell differentiation. We have extensively studied the regulation of the transcription factor STAT4 in response to IL-12, using PHA-activated human T cells isolated from healthy donors as a model. These studies include: a) characterisation of other possible signals that induced in response to IL-12, could regulate the activation of STAT4; b) a comparison between the characteristics of STAT4 activation in response to IL-12 and to Interferon-α (IFN-α); and c) study of the mechanism by which IL-12 induced STAT4 activation is potentiated by IL-2