The effect of T cell receptor specificity on CD4+CD25+ regulatory T cell function in an autoimmune setting

The studies presented in this dissertation examine how the T cell receptor (TCR) specificity of CD4+CD25+ regulatory T (Treg) cells affects their function in a mouse model of autoimmune arthritis (TS1xHACII mice). TS1xHACII mice co-express CD4+ T cells that express the transgenic 6.5 TCR, which is specific for the S1 determinant of influenza virus PR8 hemagglutinin (HA), and HA as a neo-self antigen under the MHC Class II I-Eα promoter. The majority of adult TS1xHACII mice develop inflammatory arthritis that is driven by recognition of S1 peptide by 6.5+CD4+ T cells. Notably, arthritis develops despite the presence of CD4+CD25+Foxp3 + Treg cells, including a population of 6.5+ cells that are specific for the disease target antigen S1 peptide. However, the administration of exogenous CD4+CD25+ Treg cells to pre-arthritic TS1xHACII mice can prevent arthritis in TS1xHACII mice, demonstrating that the disease is susceptible to CD4+CD25+ Treg cell activity. Interestingly, we have found that the ability of CD4+CD25 + Treg cells to suppress arthritis in TS1xHACII mice is highly dependent on the TCR specificity(s) of the Treg cell population. Polyclonal CD4 +CD25+ Treg cells (including cells that have not developed in the presence of the disease target antigen S1 peptide), but not CD4 +CD25+ Treg cells that are enriched for S1-specific 6.5+ cells are able to prevent arthritis development in TS1xHACII mice. Although polyclonal CD4+CD25+ Treg cells can suppress arthritis in TS1xHACII mice, our data suggest that successful CD4+CD25+ Treg cell mediated suppression of arthritis is remarkably sensitive to the balance of Treg cells and pathogenic 6.5+CD4+ T cells. We also present data indicating that CD4+CD25+ Treg cells that are strongly reactive for a highly expressed disease target antigen can be detrimental in the context of certain autoimmune diseases. Collectively, these studies indicate that the antigen-specificity of CD4+CD25+ Treg cells is a critical determinant of their ability to suppress arthritis in TS1xHACII mice. Moreover the data presented here also suggest that the balance of certain TCR specificities between CD4+CD25 + Treg and effector CD4+ T cells plays an important role in determining the maintenance of tolerance versus the development autoimmunity