The Effect of T Cell Receptor Specificity on CD4+CD25+ Regulatory T Cell Function in an Autoimmune Setting
Immunology and Infectious Disease
Laboratory and Basic Science Research
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.