T CELL GLYCOPROTEINS CONTROLLED BY IMMUNE RESPONSE GENES

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The highly-regulated vertebrate immune system protects animals from infectious and neoplastic diseases. Regulatory failures may result in neoplasia, infectious disease, immunodeficiency, or autoimmunity. Immune response (Ir) genes regulate immunity, and map in a cluster preserved throughout vertebrate evolution. Ir gene products are the class II proteins. Helper and suppressor T cells distinguish foreign antigen (nonself) and class II proteins (self) on other cells. We and others discovered Ir gene-controlled mouse T cell proteins. The Ir gene association strongly suggests a role in immunoregulation. One protein, I-J, occurs on suppressor T cells. Another, I-At, occurs on helper T cells. The I-J structural gene is not in the mouse chromosome 17 Ir gene cluster. We discovered the chromosome 4 Jt locus controlling the I-J protein. Whether this is the structural gene is unknown. Antibodies to I-J protein seem to block the T cell's recognition structure. The T cell receptor which recognizes class II proteins is unknown. Presumably, it would be controlled by Ir genes, but might be encoded elsewhere. The Ir-gene-associated T cell proteins may be class II protein receptors. To study their role in recognition and immunoregulation, we plan to characterize the Ir-gene-associated T cell proteins genetically and functionally. Using specific antibodies in a flow cytometric assay, we will re-examine I-J allelic strains, analyze I-Jb genetic control, test for allelic exclusion, map the I-J structural gene, and test linkages in a backcross. Cell fusions and gene transfection will determine whether the I-J-controlling genes H-2 and Jt must be active in the same cell. Analyzing chimeric T cells will test whether the genes are active in different cells. We will investigate whether the Jt locus exerts its control by influencing class II protein expression. We will study a possible chromosome 7 locus involvement. Determining the I-At protein's genetic control will extend our analysis. Finally, we will probe the function of Ir-gene-associated T cell proteins testing the hypothesis that these serve as the T cell receptor's class II protein recognition element.