Redox regulation of T cells in autoimmunity

Abstract

Autoimmune disorders affect a significant part of the population and therefore present a serious health and economic burden. One of the most common autoimmune diseases is rheumatoid arthritis (RA), affecting 0.5-1% of the population which is mediated by both genetic and environmental risk factors. A common thread throughout this thesis is the impact of various proteins on T cell signaling and how this affects autoimmune inflammation in rodents.

Studies I and II investigate the role of redox regulation on two major players in TCR signaling: PTPN22 and LAT. We targeted known redox-sensitive cysteine residues in these proteins and could thereby investigate their importance in vivo. Study I shows that PTPN22 function can be regulated by its non-catalytic cysteine 129 (C129) residue by forming a disulfide bond which protects the active site from irreversible oxidation; impaired redox regulation leads to enhanced T cell and inflammatory responses. In a similar vein, we found in Study II that cysteines 120 and 172 mediate redox regulation of LAT by affecting its phosphorylation and localization. Redox insensitivity of the LAT protein worsens T-cell dependent inflammation.

In the last two studies we have used a forward genetics approach to identify genetic determinants of RA susceptibility: In Study III we were the first to identify that loss of Sh3gl1 leads to protection from autoimmunity due to alterations in the T cell signaling pathway, thereby providing an attractive new therapeutic target. Study IV shows that polymorphisms regulating vitamin D receptor expression affect T cell activation and T cell mediated inflammation. Collectively, our results show the importance of physiological redox effects and expand the knowledge on RA genetics.