In Type 1 diabetes (T1D), the body’s own immune cells gradually destroy the insulin-producing pancreatic beta cells. The disease is influenced by genetic and environmental factors. The main trigger, however, is a false reaction of the immune system in which the immune cells do not distinguish between foreign and endogenous components such as beta cells. Normally, Foxp3+ regulatory T(Treg) cells prevent such an attack on the body’s own cells. Therefore Treg cells are referred to as the "blue helmets, the peacekeeping troops of the immune system" to maintain a state called immune tolerance. In T1D, sufficient numbers of these functional "blue helmets" are lacking to carry out this function. Consequently, beta cells are destroyed by the pathologically activated immune cells. However, the cellular and molecular underpinnings promoting this impairment of immune tolerance remain poorly understood especially in the human immune system. In my laboratory we aim to dissect mechanisms of aberrant immune activation that can interfere with tolerance induction during islet autoimmunity. To this end, we use an integrative translational research approach combining cellular and molecular immunology with immunepharmacology.
Targeting miRNA-mediated immune activation in humanized mice
On the basis of their ability to regulate cellular states including T cell activation and effector function microRNAs (miRNAs) are critical in driving overshooting immune reactions. Specifically, using T cells from children at an early stage of islet autoimmunity we recently identified miRNA181a and miRNA92a to be key players in promoting aberrant T cell activation and T follicular helper cell differentiation thereby linking impairments in Treg induction with autoimmune activation. We showed that blocking miRNA92a or miRNA181a increases Treg induction and reduces murine islet autoimmunity in the setting of NOD mice in vivo. These findings suggest that targeting miRNA92a/miRNA181a signaling could contribute to the development of innovative strategies aimed at inhibiting the signaling intermediates of T cell activation to interfere with autoimmune activation while improving Treg induction. Now, assessment of targeting miRNA92a/miRNA181a signaling in the context of a human immune system in vivo will be an important translational step to integrate the findings obtained in T cells from children with ongoing islet autoimmunity with the results from murine T1D models. To fill this knowledge gap, my laboratory recently established humanized NSG mouse models and provided direct evidence that subimmunogenic antigen application induces human Tregs in humanized mice. The present PhD project will therefore employ a synergistic interdisciplinary approach combining expertise in cellular, molecular and human immunology to study targeting miRNA-mediated immune activation in humanized NSG mice.
Scherm M et al., Mol Metab 2019, in press
Serr I et al., Science Transl Med 2018
Serr I et al., Front Immunol 2018
Kälin S et al., Cell Metab 2017
Serr I et al., Nat Comm 2016
Serr I et al., PNAS 2016