Maturation of T-cells in the thymus depends on the intracellular interpretation of signals emanating from the a T-cell Receptor (TCR). Interactions generating strong TCR signals delete autoreactive thymocytes, by negative selection, while interactions generating moderate TCR signals induce positive selection and differentiation into CD4 or CD8 single positive (SP) T-cells. Despite evidence that positive or negative selecting signals differentially regulate the degree of activation of kinases such as Erk, Jnk and p38 the molecular mechanisms that translate differences in TCR signaling into different developmental outcomes is still poorly understood and remains intensively studied. Our recent studies show that a TCR engagement activates -catenin/Tcf-signaling in wt double-positive (DP) thymocytes. Genetic manipulation of -catenin/Tcf activity in TCR transgenic mice indicates that this cascade determines the outcome of thymocyte-selection. TCR engagement in DP-cells with stabilized -catenin triggers signaling previously linked to negative-selection including a transient activation of Erk and sustained over-activation of Lat, and Jnk. This leads to induction of Bim, which mediates clonal deletion. By contrast Tcf-1 deficiency reduces Bim expression and rescues from negative-selection. Both conditional activation of -catenin and ablation of Tcf-1 yield altered TCR repertoires in peripheral T-cells. While these observations indicate that TCR signaling activates -catenin/Tcf to mediate control over thymic selection the critical molecular interaction between the two signaling cascades and the precise selection processes influenced remain to be elucidated. Our hypothesis is that TCR directly activates -catenin/Tcf signaling, by stabilizing -catenin through altered protein modification and/or localization. Consequently -catenin/Tcf activity controls the intracellular translation of TCR signals and determines the decision between positive and negative selection as well as escape from intrathymic death through agonist selection. Delineating the role of -catenin/Tcf in TCR signaling and its impact in thymocyte selection has the exciting potential to provide novel insights on the development of T-cell immunity and the shaping of the TCR repertoire. To this aim we propose to analyze the interaction between TCR and -catenin/Tcf signaling and to determine of the role of -catenin/Tcf in thymocyte selection.

R56AI059676

2004-04-01

2011-08-31