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 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 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 that is specific for the disease target antigen S1 peptide. However, prophylactic administration of exogenous CD4+CD25+ Treg cells can prevent arthritis in TS1xHACII mice, demonstrating that the disease is susceptible to Treg cell activity. Interestingly, we have found that the ability of CD4+CD25+ Treg cells to suppress arthritis is highly dependent on the TCR specificity(s) of the Treg cell population. Polyclonal CD4+CD25+ Treg cells, but not antigen-specific 6.5+CD4+CD25+ Treg cells can prevent arthritis development in TS1xHACII mice. Our data suggest that CD4+CD25+ Treg cells that are strongly reactive for a highly expressed target antigen can be detrimental in the context of certain autoimmune diseases, and 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. Degree Type Dissertation Degree Name Doctor of Philosophy (PhD) Graduate Group Immunology First Advisor Andrew J. Caton, Ph.D.