Yánez-Marcayata, Diana Carolina; (2018) The role of Hedgehog signalling and its target genes in T helper differentiation and Th2 mediated disease. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The process through which CD4 T-cells develop into Th1 and Th2 subsets has been the topic of intensive studies and many proteins are described to be involved. The Hedgehog (Hh) signalling pathway comprises a family of morphogens that are essential during mammalian organogenesis and in the development and homeostasis of T-cells. In addition, Hh signalling is involved in the differentiation of murine Th2 cells and contributes to the development of allergic airway disease. The family of Foxa2 transcription factors are Hedgehog target genes that have also been implicated in the regulation of the immune system. In this study, we investigate whether Foxa proteins are important in the process of Th1/Th2 differentiation and determine whether the deletion of Foxa2 from T-cells contributes to airway inflammation. We found that the absence of Foxa2 from T-cells might lead to Th2 differentiation and impede Th1 differentiation. Furthermore, Foxa2 expressed in T-cells contributes to Th2-mediated disease in an allergic papain asthma model. IFITM proteins are also Hedgehog target genes that are important for cellular resistance to viral infection. In our experiments, we demonstrated that IFITM proteins are also implicated in the differentiation of T helper cells. Skewing experiments demonstrated that IFITM family deficient cells expressed higher levels Th1 genes and proteins when cultured under neutral and conditions that drive differentiation into Th1 cells. Furthermore, the deletion of the IFITM family skewed T-cell responses towards Th1, ameliorating the inflammatory process of asthma in a papain mice model. Finally, we investigated the effect of Hh signalling in human T helper differentiation. Treatment of naive CD4 T-cells with Shh under Th2 skewing conditions, results in increased expression of the main Th2 transcription factor and Th2 cytokine. Taken together, these studies provide evidence that the Hh signalling pathway and its target genes play critical roles in the Th1 and Th2 differentiation and have an impact in the development of Th2 diseases such as allergic asthma.

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