Investigating a disintegrin and metalloproteinase-mediated Neuropilin 1 cleavage in autoimmune diabetes

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PROJECT SUMMARY/ABSTRACT Type one diabetes (T1D) is a chronic autoimmune disorder affecting millions worldwide and although insulin replacement therapy is lifesaving, it is not a cure.1 Characterized by immune infiltration into the Islets of Langerhan, T1D is caused by the immune mediated destruction of insulin producing β cells, resulting in an impaired ability to use and store glucose as an energy source. Therefore, immune regulation is vital in the prevention of T1D and particularly, Regulatory T cells (Tregs). Data from our lab and others suggest that Tregs a vital extrinsic mechanism of peripheral tolerance to islet autoantigens, the failure of which results in symptomatic T1D.2–8 This phenomenon is referred to as “Treg insufficiency” and is supported by evidence in both humans and animal models of the disease.9–11 Therefore, a complete understanding of the mechanisms driving the T1D-related Treg insufficiency is critical to the development of novel immunotherapeutic treatments for the disorder. Previously, our lab has demonstrated a role for the transmembrane receptor Neuropilin 1 (Nrp1, or CD304) and its ligand, Semaphorin4a (sema4a), in maintaining Treg stability in the tumor microenvironment.12 Here, we defined Treg stability as sustained function, viability, proliferation, and lineage identity. Taking these results into consideration, along with the knowledge that in humans NRP1 has been mapped to one of the T1D-susceptibility regions, we were interested in investigating the role of Nrp1 in the disease progression of T1D.9,13 Surprisingly, however, Treg-restricted deletion of Nrp1 showed no impact on the disease onset in the non-obese diabetic (NOD) mouse model of autoimmune diabetes. This was attributed to a progressive loss of Nrp1 from the surface of intra-islet Tregs which we found to be metalloprotease mediated. Of note, loss of Nrp1 is specific to intra-islet Tregs. This led us to query Nrp1 loss and, consequently, the development of a fragile Treg phenotype in the islets, as a potential mechanism for Treg insufficiency. The mechanisms promoting this ADAM mediated cleavage in the islets are still unknown, though we propose it to be factors specific to the islet microenvironment since cleavage is specific to the islet microenvironment, such as enhanced intra-islet insulin receptor signaling. We hypothesize that insulin receptor signaling drives cleavage of Nrp1 on intra-islet Tregs, therefore, inducing Treg fragility, and that this fragility can be delayed or prevented by increasing Nrp1 expression on intra-islet Tregs. Specifically, we Aim to (1) investigate the impact of insulin receptor signaling on intra-islet Tregs and to understand if insulin exposure in the islet-microenvironment drives the enhanced metalloprotease mediated elimination of Nrp1.. We also Aim to (2) To investigate if enhanced Nrp1 prevents Treg insufficiency in autoimmune diabetes. Successful completion of this proposal will provide enhanced insight into the role that Treg stability, and loss thereof, plays in T1D and may prove translationally relevant to the treatment of T1D.