While most efficacious vaccines are thought to work through elicitation of neutralizing antibodies, the pathogens that cause diseases such as AIDS and malaria are notoriously difficult to neutralize with antibodies, leading vaccine developers to test the efficacy of vaccines designed specifically to elicit strong T cell responses, in the hope that a rapid secondary T cell response could limit early dissemination of the pathogen before it has the opportunity to establish a chronic infection. These efforts are complicated by the fact that antigen-specific memory T cell populations are phenotypically heterogeneous, and the role of defined subpopulations in secondary immune responses remains hotly debated. Our MHC tetramer technology has played an essential role in defining the distribution of T cell subsets specific for a variety of pathogens, and this continues to be a central focus of the work in our laboratory. We are interested in both defining the relationships between T cell phenotypes and effector functions that can be assessed using short-term in vitro assays (that do not require amplification of T cell populations), as well as using adoptive transfer experiments in mouse models that permit in vivo testing of the efficacy of purified T cell subsets. In support of these studies, we are actively engaged in the development of new technologies that will (1) permit more rapid assessment of T cell responses to large pathogens as well as mapping of T cell epitopes and (2) permit multiparametric flow cytometry assessment of T cell phenotypes.