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 are unable to 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, multiple impairments of these “blue helmets” contribute to a loss of immune tolerance. Consequently, beta cells are destroyed by the pathologically activated immune
cells. However, the cellular and molecular underpinnings promoting these impairments in immune tolerance remain poorly understood, especially in the human immune system. In my laboratory, we aim at dissecting cellular and molecular mechanisms of immune tolerance in T1D. To this end, we make use of an integrative translational research approach combining cellular and molecular immunology with immunopharmacology.
Next generation immune modulation in Type 1 Diabetes
In the last years, we have identified a multitude of impairments in immune tolerance and various manifestations of aberrant immune activation during human and murine T1D development. From a translational but also targeting perspective, it will be essential to dissect innovative immune targeting approaches aimed at fostering Treg cells with the goal to interfere with ongoing autoimmune activation and progression. To this end, in collaboration with the Assay Development and Screening Platform we have performed a high-throughput screen (HTS) of 25.000 compounds using an in vitro Treg induction system with T cells from Foxp3 GFP reporter mice. Based on this screen, we have identified 48 Treg-inducing candidates and are currently following the eight most promising candidates in further detail. Building on these important findings, the goal of this PhD project is to dissect the Treg-fostering potential of identified drug candidates using a series of experimental systems. These experimental approaches include but are not limited to assessing Treg induction, function and stability by employing murine and human T cells, models of T1D as well as innovative humanized models. Therefore, the present PhD project will employ a synergistic interdisciplinary approach combining expertise in cellular and molecular immunology in order to assess innovative Treg targeting to interfere with T1D development.
1. Becker M, Serr I, Salb VK, Ott VB, Mengel L, Blüher M, Weigmann B, Hauner H, Tschöp MH, Daniel C. Short-term cold exposure supports human Treg induction in vivo. Mol Metab 2019, doi: 10.1016/j.molmet.2019.08.002
2. Serr I, Scherm MG, Zahm AM, Schug J, Flynn VK, Hippich M, Kälin S, Becker M, Achenbach P, Nikolaev A, Gerlach K, Liebsch N, Loretz B, Lehr C-M, Kirchner B, Spornraft M, Haase B, Segars J, Küper C, Palmisano R, Waisman A, Willis RA, Kim W-U, Weigmann B, Kaestner KH, Ziegler AG, Daniel C. A miRNA181a/NFAT5 axis links impaired T cell tolerance induction with autoimmune type 1 diabetes. SciTransl Med 2018.
3. Kalin S*, Becker M*, Ott VB, Serr I, Hosp F, Mollah MMH, Keipert S, Lamp D, Rohner-Jeanrenaud F, Flynn VK, Scherm MG, Nascimento LFR, Gerlach K, Popp V, Dietzen S, Bopp T, Krishnamurthy P, Kaplan MH, Serrano M, Woods SC, Tripal P, Palmisano R, Jastroch M, Bluher M, Wolfrum C, Weigmann B, Ziegler AG, Mann M, Tschop MH, Daniel C. A Stat6/Pten Axis Links Regulatory T Cells with Adipose Tissue Function. Cell Metab 2017, 26, 475-492 e477; * both authors contributed equally.