Lipid activated T cell Inflammation in Type 2 Diabetes

Abstract

Abstract Current mouse models of Type 2 Diabetes (T2D) do not recapitulate the complexity of the human disease. Chronic inflammation in T2D patients has been described in the literature extensively. However, there are no clear answers describing what molecules are causing this inflammation and how it contributes to disease progression. Classically, T cells are known to mediate immune responses by recognizing protein that is presented to them. Recently, T cells have been shown to respond to lipids that are presented on a molecule called CD1a. This molecule is expressed by humans and not by mice. Using mice expressing human CD1a with comparable CD1a expression to human cells, we show these humanized mice on a high fat diet have human-like T2D including liver and adipose inflammation as well as higher glucose intolerance without insulin intolerance when compared to wildtype mice. We also see elevated immune infiltration into adipose and liver tissue in high fat CD1a mice. In addition, CD1a are more likely to have smaller islet on a high fat diet relative to wildtype as well as sign of pancreatic atrophy, a hallmark of T2D progression.These data validate T cell responses to lipids via CD1a as a potential contributor to T2D and will establish a more physiologically relevant mouse model of T2D through an immunological mechanism.