Human T lymphocytes can be activated by either of two lineage specific surface structures: the T3-Ti complex and the 50KD T11 molecule. While the five polypeptide chains of the T3-Ti complex have been cloned and characterized, less information is available about the single chain 50KD T11 molecule. Recently, we have deduced the primary structure of T11 from protein microsequencing and cDNA cloning which suggests that it is divided into three domains: a hydrophilic 185 amino acid domain bearing only limited homology to T4 and V kappa molecules; a 25 amino acid hydrophobic transmembrane segment; and a novel 126 amino acid cytoplasmic domain rich in prolines and basic residues. To examine the structure-function relationship of the T11 molecule, this proposal will address four areas: 1) organization and chromosome location of the T11 gene in man and mouse; 2) expression of T11 protein by recombinant DNA technology; 3) site-directed mutagenesis of the T11 cDNA: and 4) analysis of other gene programs activated through T11 receptor triggering. Firstly, we will determine the intron-exon structure and chromosomal location of the T11 gene in man and mouse. This type of analysis will readily reveal features of important structural conservation. Secondly, as recent studies suggest that the external domain of the T11 molecule may have one or more natural ligands including the ubiquitous cell surface molecule LFA-3, the effects of the secreted T11 external domain (membrane anchorless form) on CTL effector function and T cell proliferative response will be examined. To this end, T11 will be expressed in both L cells and insect cells. Thirdly, site directed mutagenesis and transfection studies will be employed to determine functionally critical residues for ligand(s) binding and signal transduction. A proline rich area with four histidines in the cytoplasmic region is of particular interest. As triggering through the intact T11 structure resulted in transmembrane calcium flux, sodium proton antiport exchange, phosphotidyl inositol turnover and nuclear activation, the ability of mutant T11 genes to stimulate these activities will be assayed. Finally, subtractive hybridization technology will be employed to find those genes which are specifically induced upon T11 structure triggering in T lymphocytes.

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National Institute of Allergy and Infectious Diseases (NIAID)
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Allergy and Immunology Study Section (ALY)
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Dana-Farber Cancer Institute
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