Systems Biology Approach to Molecular Mechanisms of Human TGFb Induced iTreg Cell Differentiation and the Role of iTreg in Multiple Sclerosis

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Regulation of the immune response is central for human health. T helper (Th) cell subsets orchestrate the adaptive arm of the immune system and their pathological imbalances result in chronic inflammatory and autoimmune diseases. Effector cell functions are suppressed by natural or induced T regulatory cells (Treg and iTreg, respectively). One key assumption for the development of autoimmunity is a dysregulation in the functional capacity and/or development of regulatory immune cell populations. Therefore, understanding the gene regulatory pathways controlling T‐cell differentiation into functionally distinct subsets will be crucial to understand the pathogenesis of immune‐mediated diseases and to develop and understand better immunomodulatory therapies. We propose to to study the effects of TGFb 2(6) during induction of iTreg from naive human CD4+ T cells. We will study whether TGFb mediated induction of Tregs is dysfunctional and what molecular targets might underly this in Multiple sclerosis, a prototypic chronic autoimmune inflammatory disorder, where balance of peripheral immune regulation is considered key to understanding of pathogenesis and early treatment. Our objectives are: 1) To study transcriptional and epigenetic regulation of Th cell differentiation in TGFb induced Treg cells. 2) To develop integrative and dynamic models of key differentiation mechanisms, assess effects of disease related mutations, and identify points of intervention to modulate differentiation response. 3) To investigate the role of new Th cell regulators in human inflammatory disease paradigms (e.g. Multiple sclerosis) and in vivo models (humanized mice). Cutting edge technologies and carefully selected valuable patient samples and records will be exploited to address the questions. Our results are expected to reveal the key regulatory mechanisms of human immune response and pathology and potentially new opportunities for its modulation.