The T cell antigen receptor (TCR) is structurally homologous to an immunoglobulin (Ig) Fab fragment; it is a disulfide-bonded heterodimer composed of an alpha- and a beta-chain, each of which includes a variable and a constant region domain anchored in the cell membrane. Sequence comparisons by a number of groups strongly support a model of the receptor which indicates that the tertiary structure of each domain forms a classic Ig-fold. A further extrapolation of this model involves a prediction of the portions of the TCR that interact with its natural ligand, i.e., major histocompatibility complex (MHC) molecules bound with short polypeptides. Experiments are described to test models of the TCR based on an Ig structure and the further predictions of TCR-MHC interactions. In order to determine whether the TCR chains interact with an MHC-antigen ligand as predicted, we propose splicing the portions of TCR chains that correspond to Ig complementarity determining regions (CDRs) from one TCR to another. We will determine whether these hybrid TCRs can mediate the specificity of the TCR from which the CDRs originated. Data are presented showing that at least in one example this type of CDR substitution does indeed transfer antigen/MHC specificity. In order to interpret these experiments we propose an exercise in which the sequence of the TCR is used to model its structure based on the database of published Ig structures determined by X-ray crystallography. Finally, we propose techniques to cheaply produce large amounts of soluble TCR for biochemical and structural analyses. In support of the notion that TCR domains form an Ig-fold, we have shown that at least in some instances, a VH-Ig domain can substitute for a Valpha TCR domain in forming a functional receptor on T cells. We propose a medically relevant extension of these results. Hybrid TCR molecules composed of Ig heavy and light chain variable regions from an HIV gp41-specific antibody will be spliced onto the constant regions of the alpha- and beta- TCR chains. This reconstructed TCR will be examined for potential therapeutic value in the treatment of AIDS.
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