Endocrine control of T cell function and its implications for the pathogenesis of neuroinflammatory diseases
von Henrike Fischer
Datum der mündl. Prüfung:2013-06-11
Erschienen:2013-06-17
Betreuer:Prof. Dr. Holger Reichardt
Gutachter:Prof. Dr. Lutz Walter
Gutachter:Prof. Dr. Alexander Flügel
Dateien
Name:Dissertation Fischer.pdf
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Format:PDF
Zusammenfassung
Englisch
Insulin and GCs are two important endocrine regulators of mammalian body homeostasis and both impact on immune cell functions. Whereas GCs are in widespread use for the treatment of autoimmune diseases since the late 1950s, the influence of insulin is less well characterized. Nonetheless, it is undoubted that there is a link between insulin-responsiveness and immunity. Here we have shown that GCs exert a rapid effect on T cell morphology. We have identified GC-induced phosphorylation of the cytoskeleton associated ERM proteins as an important mechanism in this process, and found that it is accompanied by a loss of the polarized structure of effector T cells, a reduction in cell size and reduced capacity to conjugate with APCs. The effector T cells retract their lammellipodiae following GC treatment, which leads to impaired transmigration and presumably chemotaxis, as chemokine receptors are expressed in a polarized manner on the lammellipodiae. Additionally, we have found that this effect is dependent on the presence of the GR and on PLC activity. Furthermore we have challenged the hypothesis that insulin-responsiveness is required to allow proper T cell activation, differentiation and function. We took advantage of an inducible InsR kd to compare the functions and the survival of different T cell subsets in the presence or absence of the InsR. We could show, that the early phase of T cell activation is impaired in InsR deficient cells, whereas the InsR is dispensable during long-term activation and for overall survival. Whereas Treg cells were not affected by InsR inactivation, CD8+ T cells had a decreased lytic capacity compared to wildtype cells. So far we have no clear evidence whether the InsR also plays a role for immune responses in vivo. Collectively, endocrine control of T cell function is of considerable importance and could explain the involvement of hormones in chronic diseases and their treatment.
Keywords: T cell; neuroinflammation; Insulin; Glucocorticoids