Genetic Determination of the Ctl Receptor Repertoire

Sherman, Linda

Abstract

The objective of the proposed research if to identify all polymorphic genetic loci which contribute to the determination of the receptor repertoire of cytolytic T lymphocytes (CTL) and to elucidate their mechanisms of action. By studying the fine specificity of primary CTL clones specific for the H-2Kb molecule we previously demonstrated that the response of an inbred strain is characterized by both a large number of clonotypes, each of which recurs at a low frequency, as well as a small number of highly recurrent clonotypes. These recurrent specificities serve as phenotypic markers and thereby permit comparison of repertoire between strains of defined genetic non-homology. We previously demonstrated that both MHC and Igh linked genes affect the expressed receptor repertoire. By comparing the responses of strains which are recombinant in these genetic regions, we will further localize the precise genetic loci which are involved. In addition, we will evaluate any potential contribution by non-MHC, non-Igh background genes and also study clonotype expression in heterozygous individuals. In order to distinguish between mechanisms which operate at the intracellular vs extracellular (environmental) level, we will compare the repertoires of CTL precursors which are genotypically different yet have matured in an identical environment. To this end we will construct tetraparental radiation chimeras by reconstituting (A x B)F1 individuals with an equal mixture of A plus B stem cells and then independently assess the repertoire of A and B type cells.