Long-term acceptance of transplanted solid organs is difficult to achieve and the mechanisms that warrant graft tolerance are still poorly understood. It is believed that if tolerance prevails, many graft-specific lymphocytes must die, whereas the rest of these effector cells have to be overpowered by a subpopulation of regulatory CD4⁺ T cells. Currently it is also unknown what mechanisms, at the level of a single lymphocyte, direct the CD4⁺ cell to become a graft invader or graft defender. The most individual feature of lymphocytes is their receptors for antigen. Each person has millions of lymphocytes equipped with unique antigen receptors. Therefore it is expected that the properties of these antigen receptors on individual lymphocytes determine cell fate during an alloresponse.

In our project, we propose to use exclusive genetically manipulated mice that although having a normal number of lymphocytes, these cells express only two to three hundred different receptors for antigens. Using these mice, we propose to determine if lymphocytes functionally committed to attack or to defend a graft express the same or different antigen receptors. Next we will determine if these receptors sense the same or different peptides that remain bound to MHC molecules, and can activate CD4⁺ lymphocytes. This research should reveal the mechanisms behind the functional commitment of lymphocytes during an alloresponse and examine how affinity of the antigen receptor for alloantigens and self-antigens influence lymphocytes fate.