Natural Killer Cell Re-Modeling of the Extra-Cellular Matrix by the Degradation of Hyaluronan: Potential Role in Type 1 Diabetes

Abstract Natural Killer (NK) cells have been shown to contribute to early insulitis during development of Type 1 Diabetes (T1D). We previously identified increased Hyaluronan (HA) deposition within inflamed pancreatic islets, indicative of remodeling of the extra cellular matrix (ECM) of which HA is a component. NK cells express CD44, a ligand for HA, and granzymes known to facilitate extravasation through the ECM. Thus, we asked whether NK cells may directly interact with the ECM, potentially contributing to HA modification in pancreatic islets. Isolated NK cells activated with IL-12, IL-15, and IL-18 up-regulated Has3, CD44, and Hyal1: genes related ECM re-modeling suggesting that NK cells may act upon the ECM. To test NK-ECM interactions, we used a co-culture system of stimulated NK cells and HA producing fibroblasts. We found down-regulation of Hyaluronidases Hyal1 and Hyal2 and up-regulation of HA Synthases Has1 and Has2. These results are consistent with NK cell modulation of ECM, that was also indicated by depletion of the fibroblast cell layer. Comparatively, CD4 and CD8 T cells did not show depletion of the cell layer and differed in the degree and composition of ECM related transcripts. Together, these data suggest that NK cells play a critical role in ECM re-modeling; this NK-ECM interaction may contribute to pancreatic inflammation in the setting of T1D.