NON-H-2 HISTOCOMPATIBILITY GENES AND ENCODED ANTIGENS

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Histocompatibility (H) antigens encoded by genes mapping outside of the major histocompatibility complex comprise a formidable barrier to successful tissue transplantation. Although the family of non-H-2 H antigens in the mouse has served as an important model system for studying the regulation of the T cell response, virtually nothing is known of the origins and functions of these antigens. This continuing program has been aimed at elucidating the mechanisms of responses to multiple and single H antigens. We have recently discovered that H antigens are generated by germline integration of retroviruses and tumor viruses. The proposed research plan is a multi-faceted approach to understanding the mechanisms and regulation of the T cell response to H antigens and the identification of members of this important family. The first experiments are aimed at revealing the basis for the preferential, in vitro T cell response to immunodominant antigens and its relevance to T cell responses in vivo. Potential roles for (1) preferential presentation of dominant antigens by H-2K/D molecules, (2) differences in affinity and number of IL-2 receptors on T cells specific for dominant and dominated antigens, and (2) different classes of dominant antigens for helper and cytolytic T cells will be investigated. The T cell response to single H antigens will be analyzed to determine (1) the role of discrete regions of H-2K molecules in H antigen presentation and determination of Ir gene status, (2) the effects of T cell receptor V genes used by H antigen-specific T cells on antigen specificity and H-2 restriction, and (3) the relationship between the mechanisms of in vivo and in vitro T cell responses. These studies will be complemented by the cloning and identification of non-H-2 H genes. The observation that the SV40 T-antigen is seen as an H antigen in transgenic mice will be extended by determining the effects of different promoters and flanking regions on its expression as an H antigen. The association between a new mammary tumor virus and a mutant H antigen will be confirmed by cloning this retrovirus to assess its ability to encode this H antigen. The relationship between coat color and H gene mutations will be extended to confirm that coat color mutant reversions lead to the loss of H antigens. Finally, retroviral vectors will be employed as insertional mutagens to inactivate a single H gene; the cloning of the integrated retrovirus will facilitate the first cloning of an H gene from a cosmid library.