The T cell repertoire is composed of two distinct properties - the recognition specificity of the TCR heterodimer and the functional response of the cell after TCR stimulation. It is now clear that once a particular TCR heterodimer is expressed on the T cell surface, the antigen specificity is frozen for all the clonal progeny of that cell. The functional responses available, however, are quite extensive and range from programmed cell death to initiation of distinct modalities of active immune response. This proposal is designed to elucidate the mechanisms that determine the selection among possible functional responses and the clonal stability of such selection events in vivo. The experimental approach will be to examine the in vivo responses and long-term fate of antigen-specific alpha beta-TCR transgenic T cells transferred into normal mice using sensitive, single-cell analytical methods. A central focus will be the comparisons of naive versus antigen-experienced T cells following in vivo antigen responses initated by defined modes of antigen delivery. The broad long-term objective of this study is to determine the in vivo interactions that determine the functional activity of T cells so that these interactions can be altered to achieve more clinically useful immune responses (or lack of immune responses) in clinical medicine.
