The overall goal of this project involves the establishment and analysis of a new autoimmune(AI) mouse model where T cells that are self-reactive escape deletion due to a defect in the presentation of tissue specific antigens (TSAs) in the thymus. The Autoimmune REgulator (AIRE) gene is responsible for """"""""turning on"""""""" the production of TSAs. Mice lacking this gene develop spontaneous Al diseases comparable to patients with Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED), who surfer from various Al diseases of the endocrine and non-endocrine organs. Al diseases as a whole, are the third most common major illness in the United States. The most common autoimmune diseases affect more than 8.5 million (or 1 in 31) Americans. Therefore, the need to better understand, treat, and ultimately prevent all diseases is essential. The National Institute of Health (NIH) supports the basic and applied research that leads to the development of new therapies, vaccines, diagnostic tests, and other technologies for this purpose. In order to determine the """"""""culprits"""""""" of Al, namely the self-reactive CD4+ T cells, as well as the role that the body's peripheral tolerance mechanisms play, primarily FoxP3+ regulatory cells (TR cells), we had to develop a way to """"""""track"""""""" these cells and their interactions during disease initiation and progression. At the cellular level, autoimmune disease is viewed as an imbalance between the self-reactive T cells and the suppressive TR cells. Considering that the normal T cell receptor (TCR) repertoire is too diverse for tracking, our mouse model houses a functional TCR with an alpha chain that naturally rearranges (Va2 -Ja26/Ja2) and a rearranged fixed beta chain. This limits the repertoire allowing us to characterize the TCR repertoire easier. Lastly, we are very interested in the TR cell population and its interactions with self-reactive T cells, by attaching the fluorescent protein GFP to the FoxP3 promoter, all TR cells emit a green fluorescent signal which makes them easily distinguishable for tracking and conducting experiments. Not only will this investigation lead to a better understanding of the role of TR cells in autoimmunity but it may also reveal the """"""""key"""""""" receptors responsible for specific all diseases.
| Daniely, Danielle; Kern, Joanna; Cebula, Anna et al. (2010) Diversity of TCRs on natural Foxp3+ T cells in mice lacking Aire expression. J Immunol 184:6865-73 |
