In 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 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“ in order to maintain a state called immune tolerance. In T1D, sufficient numbers of these “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 immune tolerance impairment remain poorly understood. 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.
The role of TRPV1 for Foxp3+ regulatory T cell induction in diabetes
Recently, TRPV1, a Ca2+-permeable channel was shown to be functionally expressed in CD4+ T cells. Here, it functioned as a non-store-operated Ca2+ channel and contributed to T cell receptor (TCR) – induced Ca2+ influx, T cell receptor (TCR) signaling, T cell activation and the acquisition of pro-inflammatory properties by CD4+ T cells. However, it remains elusive whether TRPV1 contributes to the aberrant activation of CD4+ T cells and the observed Treg impairments during islet autoimmunity and T1D. The present PhD project will employ a synergistic interdisciplinary approach combining expertise in T cell/Treg immunology with pharmacology, TRPV channels and cellular electrical activity to dissect the role of TRPV1 in Treg induction and function in diabetes. Specifically, the project will address the following questions: Is there an aberrant expression/activation of TRPV1 channels in CD4+ T cells vs. Treg cells during murine and human islet autoimmunity and diabetes? Do TRPV1 channels contribute to the impaired Treg induction, function and stability during islet autoimmunity and diabetes? Can pharmacological TRPV1 inhibition improve Treg induction potential during islet autoimmunity and diabetes? Does TRPV1 inhibition impact the development or progression of islet autoimmunity in murine models of diabetes?
Serr I et al., Science Transl Med 2018
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Serr I et al., PNAS 2016