Investigating the Role of CD137 Ligand in the Pathogenesis of Type 1 Diabetes

Pathogenesis of type 1 diabetes (T1D) involves various interactions between genetic and environmental factors. The gene encoding the co-stimulatory molecule CD137 is located within the Idd9.3 T1D susceptibility locus and contributes to diabetes progression in NOD mice. We have previously shown that CD137 expression in T cells has dual functions: CD4+CD137+ T cells negatively regulate T1D development while CD8+CD137+ T cells showed potent diabetogenecity. The protective function of CD137 in CD4+ T cells is likely due to the significant amounts of soluble CD137 (CD137) produced by Foxp3+ Tregs. The interaction between CD137 and its ligand (CD137L) induces two signaling pathways, forward one driven by CD137 and the reverse signaling mediated by CD137L, both of which modulate T cell function. Here, we study the impact of CD137L deficiency on T1D to gain further insight into disease pathogenesis. We successfully generated a mouse strain with the NOD background and knockout of the gene encoding CD137L (Tnfsf9) using CRISPR/Cas9 technology. Relative to wild type NOD, Tnfsf9^-/- mice showed significant delay in T1D development, less islet-infiltrating autoreactive CD8 T cells, reduced high-avidity IGRP autoreactive CD8 T cells in the spleen and pancreatic lymph node, and less inflamed islets. Interestingly, we detect significant increase in serum levels of sCD137. Furthermore, we could not detect differences in CD137+ Treg populations between NOD and Tnfsf9^-/- mice. In bone marrow transfer experiments, CD137L deficiency in either hosts or donors was able to suppress T1D development. Tnfsf9^-/- and wild type T cells showed similar capacity to induce T1D in NOD.Rag1-/- recipients. We are working on identifying the cellular source of increased sCD137 and the mechanism behind this elevation. We direct our efforts to understand how CD137-CD137L interaction can modulate T1D pathogenesis and how to translate the data from NOD mouse to understand the pathogenesis of human diabetes.