T Cell Activation

We are interested in understanding how T cells and NK cells recognize their targets and how this recognition event is translated into an appropriate immunological response. Our general approach is to combine biochemical, genetic analyses with modern imaging methods which are essential to understand signaling at the single cell level. Our current focus is in the following areas:

  1. What is the function of the immunological synapse? Our working hypothesis is that the sensitivity and specificity of T cells recognition is mediated by the formation of the mature immunological synapse. Our mathematical modeling suggests that the synapse inhibits signaling by strong ligands and enhances the recognition of weak ligands. This could play a role in enhancing responses during inflammation but also could result in autoimmunity.
  2. What controls the polarization of T and NK cells? T cells and NK cells polarize their cytoskeletal apparatus when they recognize an appropriate target cell. What are the elements of the T cell signaling machinery that mediate the polarization of the T cell? What is the function of T cell polarization? To enhance killing? To enhance the secretion of cytokines? To direct vesicular trafficking to the immunological synapse?
  3. What is the role of the immunological synapse in autoimmunity? Our data suggest that the formation of the mature immunological synapse can enhance the recognition of antigens not normally recognized by T cells. Our work suggests that cytokines like IL-12 and the expression of receptors like NKG2D can enhance the formation of immunological synapses. We suspect that this can sometimes allow for the reactivity to self-antigens and potentially autoimmunity. We have generated transgenic mouse models to test this idea.
  4. What controls the digital/analog activation of T cells? Is the activation of T cells digital or analog? In other words, do T cells respond in an all or none fashion to antigen (digital) or can an individual T cell respond weakly to a weak antigen, moderately to a moderate antigen or strongly to a strong antigen (analog). At least in vitro, our work suggests that both responses are possible. We wish to know that mechanisms determine which type of response a T cell makes.