Repertoire of antigen receptors (TCRs) on T cells is shaped by interactions between TCRs and MHC molecules bound with peptides of self and non-self origin. In thymus, these interactions promote differentiation of immature T cells with TCRs with low/intermediate affinity for self-MHC/peptide complexes. In the periphery, such interactions warrant survival of naive T cells, or provoke activation that leads to expansion and terminal differentiation of responding T cells. As the immune response widen, responding T cells may become short-lived effector cells, long-lived memory T cells or convert into nonresponsive, regulatory CD4 + T cells. Because many different TCRs with shared antigen specificity are expressed on activated T cells, it is difficult to understand how the features of TCR structure or affinity to MHC/peptide ligands regulate T cell responses. To study how properties of individual TCR control T cell development and function, we made mice expressing the mini-repertoire of TCRs (TCR mini) that can be comprehensively monitored during development in thymus and further differentiation in the periphery. The cells bearing TCR mini are almost exclusively CD4 +, can mature in mice expressing class II MHC (A b) bound with many or one peptide(s), and are biased to recognize the defined Ab/peptide complex as strong agonist. Using these unique in vivo model we will determine how selecting MHC/peptide ligands in thymus affects diversity and function of self-selected CD4+ T cells. We will also examine the thymic origin of self-reactive CD4 + T cells. These latter experiments will be performed using CD4 + T cells isolated from TCR mini mice with impaired negative selection. Finally we also purpose to investigate how the intrinsic features of TCRs skew T cells terminal differentiation towards effector, memory of regulatory cells. This is the first model where development and function of CD4 + T cells with semi diverse repertoire of TCRs and predictable specificity for selecting and antigenic ligand can be monitored. We believe that these studies will reveal how TCR/MHC/peptide interactions govern the function and providence of T cells in vivo.
| Kuczma, Michal; Podolsky, Robert; Garge, Nikhil et al. (2009) Foxp3-deficient regulatory T cells do not revert into conventional effector CD4+ T cells but constitute a unique cell subset. J Immunol 183:3731-41 |
| Pacholczyk, Rafal; Kern, Joanna; Singh, Nagendra et al. (2007) Nonself-antigens are the cognate specificities of Foxp3+ regulatory T cells. Immunity 27:493-504 |
