Impact of insulin receptor signaling on T cell function and adaptive immunity

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Type 2 diabetes mellitus (T2DM) is a severe problem of western societies. While angiopathies account for most complications, problems are also caused by the compromised immune system of T2DM patients. Activated T cells express insulin receptors (INSR) and downstream signaling molecules, which is presumably required for an adequate immune response. To investigate the role of the INSR for T cell function we will use inducible knock-down rats allowing for its inactivation after Doxycycline administration. Initially, we will determine whether the function of T helper, cytotoxic T and regulatory T cells is compromised in the absence of the INSR. In the second part, we will investigate the signaling pathways employed by the INSR in T cells and challenge our hypothesis that it may serve to enhance glucose mobilization in concert with CD28. Antigen-specific T cells will be analyzed in two models concerning their migratory behavior, which is a particularly energy-demanding feature of effector cells. Finally, we will generate hematopoietic stem cell chimeras where gene inactivation is limited to the immune system to study the impact of INSR expression on two distinct inflammatory diseases. To this end, we will induce experimental autoimmune encephalomyelitis (EAE) as a typical model for cellular immunity, and allergic airway hypersensitivity (AAH) as an example of a humoral immune response. Collectively, these analyses should provide insight into the role and mechanism of INSR signaling in the immune system and help to better understand the compromised immune status of T2DM patients.