DYSREGULATION OF THE IMMUNE SYSTEM: EXHAUSTED T REGULATORY CELLS MAY PROMOTE PATHOGENIC TH17 CELLS IN RHEUMATOID ARTHRITIS
AuthorTankersley, Trevor Nolan
AdvisorWu, Hsin-Jung Joyce
MetadataShow full item record
PublisherThe University of Arizona.
RightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
AbstractRheumatoid arthritis (RA) is a disease in which autoreactive antibodies target the joints and lungs of an individual leading to joint swelling, bone remodeling, and lung fibrosis. The pathogenic component of RA is ROR-γt+ T Helper 17 (TH17) cells whereas FOXP3+ T regulatory (Treg) cells play a protective role in RA. A double positive (DP) T cell population, expressing ROR-γt and FOXP3, is present in the lungs of RA mice that are thought to derive from and behave like Treg cells. These DP cells express high levels of c-MAF, a key transcription gene involved in self-tolerance. T cell exhaustion is characterized by an inability to perform normal cellular function and increased expression of inhibitory signals due to chronic antigen exposure, which may contribute to RA due to constant exposure to self-antigen. We hypothesize exhaustion in Treg cells impairs their ability to suppress pathogenic TH17 cells resulting in exacerbated RA disease and in RA, the TH17 cells are less inhibited leading to the expansion of pathogenic cells. To address this hypothesis, we model RA using K/BxN mice inoculated with Segmented Filamentous Bacteria (SFB). The presence of SFB expands TH17 cells that are specific for self and SFB antigens promoting the development of RA pathology. Using this model, we show that Treg and DP cells express high levels of PD1, an exhaustion marker, and Nur77, a marker indicating T cell receptor (TCR) signaling, indicating they are stimulated but they express more inhibitory markers. There were no significant trends in other exhaustion markers in Treg cells. Whereas, TH17 cells express less PD1 and Nur77, indicating that the TCR is not as highly activated and they are less inhibited. We also noted that there was an increased level of c-MAF expression in the DP cells in both lung and spleen. Splenic TH17 and DP cells from K/BxN mice inoculated with SFB express less TIM3, a co-inhibitor marker indicating exhaustion, indicating that the TH17 cells may be less suppressed in SFB+ mice. In conclusion, we observed both cell type- and commensal-specific regulation on T cell exhaustion markers and TCR signaling strength.