T cell recognition is a central event in the development of most immune responses, whether appropriate or inappropriate (i.e. autoimmune). We have particularly focused on characterizing the types of protein-protein interactions that are involved when T cell receptors recognize antigenic peptide/histocampatibility molecule complexes. We have found that the way in which T cell receptors recognize their ligands differs in at least two major respects from immunoglobulins - 1) the topology is very restricted, in that only V-J junctional regions (CDR3 loops) seem to be important in peptide contact, and 2) that the affinity of this interaction is very low, significantly lower than other cell-surface recognition molecules and far lower than most antibodies. These results have interesting implications for the evolution of antigen receptors and particularly for the sequence of molecular events that leads up to and results in T cell activation. We have been following up the affinity measurements with a number of experiments designed to elucidate the protein-protein interactions that must occur at the cell surface between the T cell receptor, peptide/MHC complexes and other molecules during recognition. Complementary to this are systems we have established to study the induction of a T cell response both in vivo where we can follow antigen specific T cell populations directly as they differentiate into ‘memory’ T cells and in vitro, where we can induce quiescent T cells to go through at least some of these stages of differentiation. In order to understand how lymphocyte differentiation is controlled genetically, we have also pursued subtractive cDNA cloning approaches to isolate genes that may be initiating changes in cell phenotype. Analyzing late B cell differentiation, we have isolated a gene known as Blimp-1 (for B lymphocyte induced maturation proteins) which is a member of the zinc finger family and converts B cells into Ig secretory or plasma cells. We are very interested to know the manner in which this is accomplished. As there are approximately 50-100 genes turned on or off during the B cell to plasma cell transition this may be a much simpler system to study than any described to date.