Redox regulation of T cells in autoimmunity

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.

List of scientific papers

I. Jaime James, Yifei Chen, Clara M. Hernandez, Florian Forster, Markus Dagnell, Qing Cheng, Amir A. Saei, Hassan Gharibi, Gonzalo Fernandez Lahore, Annika Åstrand, Rajneesh Malhotra, Bernard Malissen, Roman A. Zubarev, Elias S.J. Arnér, Rikard Holmdahl. Redox regulation of PTPN22 affects the severity of T cell dependent autoimmune inflammation. [Manuscript]

II. Jaime James*, Gonzalo Fernandez Lahore*, Clara M. Hernandez, Florian Forster, Bernard Malissen, Rikard Holmdahl. Redox regulation of LAT enhances T-cell mediated inflammation. *Equal contribution. [Manuscript]

III. Ulrika Norin, Carola Rintisch, Liesu Meng, Florian Forster, Diana Ekman, Jonatan Tuncel, Katrin Klocke, Johan Bäcklund, Min Yang, Michael Y Bonner, Gonzalo Fernandez Lahore, Jaime James, Klementy Shchetynsky, Maria Bergquist, Inger Gjertsson, Norbert Hubner, Liselotte Bäckdahl, Rikard Holmdahl (2021). Endophilin A2 deficiency protects rodents from autoimmune arthritis by modulating T cell activation. Nature Communications. 12(1):610.
https://doi.org/10.1038/s41467-020-20586-2

IV. Gonzalo Fernandez Lahore, Bruno Raposo, Marie Lagerquist, Claes Ohlsson, Pierre Sabatier, Bingze Xu, Mike Aoun, Jaime James, Xiaojie Cai, Roman A Zubarev, Kutty Selva Nandakumar, Rikard Holmdahl (2020). Vitamin D3 receptor polymorphisms regulate T cells and T cell-dependent inflammatory diseases. Proceedings of the National Academy of Sciences. 117(40):24986-24997.
https://doi.org/10.1073/pnas.2001966117