We are interested in studying the intracellular signalling pathways that contribute to the regulation of T cell development and activation. T cells are directly involved in responses against intracellular pathogens, and tumors, and play a fundamental role in the regulation of B cell responses against extracellular pathogens. Disregulation of T cell function, whether by defect or by excess, results in dire consequences for the organism (immunodeficiency, autoimmunity).

Each developing T cell expresses a unique receptor (T Cell Receptor) that interacts with molecules of the major histocompatibility complex (MHC) associated with short peptides. The TCR determines the antigen specificity of the T cell and is the most important element in the regulation of T cell development and function. Signals derived from the TCR may induce several different cellular responses depending on the stage of differentiation of the T cell and on its prior antigen recognition history. This heterogeneity of outcomes provoked by the stimulation of a single class of receptor is conceptually perplexing, and nowhere more so than in the process of antigen-driven thymocyte selection, where ligand occupancy of the TCR may result in activation-induced apoptosis (negative selection) of immature thymocytes, or in their survival and further differentiation into mature T cells (positive selection). Though the existence of these selective events has been documented extensively, it remains puzzling that signals transmitted through the same receptor in seemingly identical cells may provoke either death or survival. Hence, the biochemical signals elicited by ligand occupancy of the TCR must either vary with the stimulating antigen, or must be interpreted flexibly in the context of other receptor-mediated signaling processes. Our research interests are focused in elucidating the role that different signal transduction pathways downstream the TCR play in the control of lymphocyte differentiation.

We have focused so far on the signaling requirements during thymocyte selection. Using dominant-negative variants of signal transduction molecules specifically expressed as transgenes in the T cell lineage, we have shown that the Ras/MAPK pathway plays a pivotal and specific role during T cell development. In particular, expression of dominant-negative forms of Ras and Mek blocks positive selection of T cells, while negative selection, as well as the generation of other T cell lineages, is completely unaffected. These results demonstrate that the TCR is able to deliver qualitatively different signals to the cell in response to interactions with MHC+peptide and that these signals determine the fate of the T cell. The research projects that we intend to pursue build upon this system and try to understand better the signaling networks that control the behavior of T cells.

In mature circulating T cells, as in thymocytes, TCR stimulation may provoke different cell responses (proliferation, anergy to subsequent stimuli, cell death).We are interested in extending the study of the role of different signal transduction pathways in cell fate commitment to these mature cells. For this kind of experiments, whether performed in T cell clones or in whole animals, it is desirable to control the moment when the chosen pathway is blocked, to avoid interference with previous developmental stages. We are doing this by placing the dominant negative transgenes under the control of inducible promoters whose expression can be regulated in whole animals. The combination of inducible transcriptional regulatory elements driving defined, dominant-negative transgenes, will greatly facilitate the analysis of signals underlying anergy, activation and differentiation in the lymphoid lineage.