T cells developing in the thymus undergo both positive and negative selection before they enter the periphery. Positive selection ensures cells will recognize self-MHC whereas negative selection removes T cells with high affinity for self-MHC. Negative selection of T cells occurs when thymocytes with high affinity for self are presented their cognate antigen. These high affinity interactions lead to activation of pro- apoptotic molecules including Bim and ultimately lead to apoptosis. However, some T cells that express self-reactive T cell receptors (TCR) can escape into the periphery. It is clear that in many cases the escape of self-reactive T cells contribute to the development and pathology of autoimmune diseases. We have developed a Nur77 transgenic reporter mouse that specifically expresses GFP in T cells in response to TCR stimulation and not inflammatory signals. The level of GFP in T cells in the steady state is low and is dependent on TCR interactions with self-peptide MHC. Using this novel tool to measure the level of self- reactivity in T cells we will stud the process of clonal deletion. Crossing the Nur77GFP mouse to mice deficient in Bim will allow us to enumerate and characterize cells that are normally deleted during negative selection. Using this model we will also determine the contribution of different antigen presenting cell types of the thymus in deletion of self-reactive T cells. A similar approach will be applied to quantitat the escape of self-reactive T cells in autoimmune disease prone NOD, Aire?, and PTPN22 variant allele mice. Altogether, the Nur77GFP mouse will allow us to quantitate and characterize cells that are normally deleted from the T cell repertoire and thus provide novel information about the proportion of the repertoire that undergoes positive and negative selection, and test specific hypotheses about the loss of central tolerance in various autoimmune disease models.
Our studies will focus on T cells specific for self-antigens in the context of tolerance and autoimmunity. Using a novel reporter mouse that directly reports T cell receptor stimulation we will study clonal deletion of self-reactive cells and defects in clona deletion leading to the development of autoimmune diseases. Our studies will provide crucial insight into clonal deletion and escape of the self-specific T cells and will ultimately increase te understanding of the events leading to autoimmunity.
|Sawicka, Maria; Stritesky, Gretta L; Reynolds, Joseph et al. (2014) From pre-DP, post-DP, SP4, and SP8 Thymocyte Cell Counts to a Dynamical Model of Cortical and Medullary Selection. Front Immunol 5:19|