The T-cell repertoire is composed of two distinct properties - the recognition specificity of the TCR heterodimer and the functional response of the T-cell after TCR stimulation. It is now clear that once a particular TCR heterodimer is expressed and successfully selected during thymic development, the antigen specificity is frozen for all the clonal progeny of that cell. The potential functional responses in the post- thymic environment are quite extensive and range from programmed cell death to initiation of distinct modalities of active immune response this application 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 utilize sensitive single-cell analytical methods to examine the in vivo responses and long-term fate of antigen-specific alpha/beta TCR transgenic T-cell transferred into normal, syngeneic hosts. A central focus will be the comparisons of naive versus antigen- experienced cells following in vivo antigen responses initiated 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 rational manipulation of the immune response (or lack of immune responses) in clinical medicine.
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