Heterogeneity in Immune Responses: CD74’s Role in β-Cell Vulnerability

• Applicants: Professor Nikolay Ninov, Ph.D.; Teresa Rodriguez-Calvo, Ph.D.
• Subject Area: Endocrinology, Diabetology, Metabolism ; Cell Biology
• Term: since 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 415464617

Type 1 Diabetes (T1D) is an immunological disease leading to the selective destruction of the pancreatic β-cells and hence the inability to produce insulin and to regulate blood sugar. Classically, the adaptive immune system has been accused of being the prime culprit for the initiation of β-cell destruction in Type 1 diabetes. However, new evidence advocates that β-cells themselves may contribute to the auto-immune process. The question arises whether β-cells are simply an innocent bystander or whether their dysfunctional states actively instigate their own destruction. In addition, it is currently unknown why β-cells are targeted so specifically by the autoreactive T-cells, whereas other endocrine islet cells, such as alpha and delta-cells are spared. Moreover, a striking but so far inexplicable feature of T1D is the apparent heterogeneity in the destructive process in terms of β-cell content and degree of infiltration (insulitis) – a given islet can be mostly devoid of β-cells and infiltrated by immune cells, whereas a neighboring islet can be completely intact with a full set of β-cells and lack of T-cell infiltration. The mechanisms underlying this heterogeneity remain a mystery. We propose that a heterogeneity in the immune-regulatory properties of β-cells leads to selective vulnerability of subsets of β-cells. To address our hypothesis, the Ninov group (expert in islet biology) and Rodriguez-Calvo (expert in human pancreas analysis) will join efforts to investigate how a key immune regulator expressed on β-cells shapes their survival and interactions with the immune system. We will focus on the Cluster of Differentiation 74 (CD74), which we have implicated in β-cell vulnerability in T1D during the previously funded project. . CD74 has dual functions that makes it a relevant candidate to mediate the crosstalk between β-cells and the immune system. On the one hand, CD74 responds to extracellular signals, such as the Macrophage Migration Inhibitory Factor (MIF). On the other hand, CD74 facilitates antigen presentation through its role in MHC class II assembly, being the invariant γ-chain. Our joint preliminary data from zebrafish, β-cell lines, a mouse model of T1D, and humans with T1D point to an important role for CD74 in mediating selective β-cell vulnerability and destruction in T1D. The goal of this proposal is to answer outstanding questions in four complementary aims: Aim 1. Defining the CD74 upstream and downstream signals controlling β-cell survival. Aim 2. Defining the role of CD74 in establishing β-cell and immune cell crosstalk. Aim 3. Defining the role of viral infection in triggering CD74 expression in β-cells. Aim 4. Defining CD74 expression-dynamics during the course of T1D progression in humans.

• DFG Programme: Research Grants