There is conflicting information regarding the role of natural killer (NK) cells in the development of Type 1 Diabetes (T1D).  NK cells represent an important effector arm against viral infection, and mounting evidence suggests that viral infection plays a role in the development of T1D in at least a portion of patients.  NK cells of diabetes prone NOD mice express high levels of the pro-inflammatory mediator 12-lipoxygenase (12-LO), and decreased levels of stimulatory receptors.  NK cells of 12-LO deficient NOD mice, conversely, express significantly higher levels of stimulatory receptors.  We previously found that 12-LO was upregulated in the pancreas of both T1D and T2D donors with insulin-containing islets.  It is not clear how this 12-LO becomes upregulated, and whether or not additional sources of 12-LO may contribute to diabetes pathogenesis.

Therefore, we propose to study NK cells that reside in the duodenum of non-diabetic, T1D, and AAb+ donor samples.  These cells will be characterized for their mRNA expression levels of anti-viral responses, as well as the expression of 12-LO and various key NK cell receptors.  Further studies will assess the functionality of NK cells from different donors with respect to their ability to produce IFN-gamma and lyse target cells.  Given the direct connection of the duodenum to the pancreas via the bile duct, there is a great potential for the immune cells in this area of the gut to influence the development of autoimmunity.