Project: Signalling pathways and gene regulatory networks responsible for Th17 cell differentiation

Lymphocytes are central for the regulation of an immune response. CD4+ T lymphocytes can differentiate to functionally distinct subsets and classified based on their cytokine secretion profiles as well as other properties. Proper regulation and balance between various lymphocyte subsets is central for the appropriate function of the immune system and required e.g. for host defence against pathogens or cancer as well as protection from autoimmune diseases. Recently, a new effector CD4+ T cell subset Th17 was discovered and named according to the main cytokine they secrete, IL17. Besides being involved in host defence to extracellular pathogens, Th17 cells play a central role in the pathogenesis of several autoimmune diseases such as rheumatoid arthritis, experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis, rheumatoid arthritis and others including inflammatory diseases in human and experimental mouse models. The cellular response to an external stimulus is mediated through a series of overlapping networks that include the signalling network,and transcription factor control at genome level, and the gene regulatory network where e.g. miRNAs and alternatively splicing play an important role. In this project we will study these networks during the differentiation of Th17 cells combining genome-wide experimental and computational approaches. We expect that our project results in the identification of the key regulatory components and hubs, or the pathways that they participate in, which may provide targets for rational chemotherapy either for the immune-mediated diseases described above, or for enhancing protective immunity against infectious agents. Our multidisciplinary consortium provides cutting-edge complementary expertise to achieve the goals.

Acronym	LymphoSys
Project Results (after finalisation)	Lymphocytes are central for the regulation of an immune response. CD4+ T lymphocytes can differentiate to functionally distinct subsets and classified based on their cytokine secretion profiles as well as other properties. Recently, a new effector CD4+ T cell subset Th17 was discovered and named according to the main cytokine they secrete, IL17. Besides being involved in host defense to extracellular pathogens, Th17 cells play a central role in the pathogenesis of several autoimmune diseases. In this project we aimed at identifying the underlying regulatory mechanisms that determine the steps required for achieving the Th17 phenotype in mouse and human T cells. We used systems biology approaches, such as microarray and next generation of sequencing technologies combined with computational data integration in this study. We generated a detailed kinetic gene expression data set to define the steps involved in regulating human and murine Th17 cell differentiation. Close collaboration among immunologists and computational scientists enabled us to compare the common and distinct regulation of human and mouse Th17 differentiation.
Network	ERASysBio+
Call	ERASysBio+-2008-01

Project partner

Number	Name	Role	Country
1	University of Turku	Coordinator	Finland
2	MRC National Institute for Medical Research	Partner	United Kingdom
3	Tampere University of Technology	Partner	Finland
4	The Netherlands Cancer Institute	Partner	Netherlands