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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI016052-09
Application #
3126533
Study Section
Immunobiology Study Section (IMB)
Project Start
1979-08-01
Project End
1988-01-31
Budget Start
1987-08-01
Budget End
1988-01-31
Support Year
9
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Wistar Institute
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Wettstein, Peter J; Borson, Nancy D (2007) Distributions of single nucleotide polymorphisms in differential chromosome segments of congenic resistant strains that define minor histocompatibility antigens. Immunogenetics 59:631-9
Wettstein, Peter J; Strausbauch, Michael; Borson, Nancy (2007) Repertoires of T cell receptors expressed by graft-infiltrating T cells evolve during long-term recall responses to single minor histocompatibility antigens. Int Immunol 19:523-34
Wettstein, Peter J; Borson, Nancy D; Park, Jewn G et al. (2005) Cysteine-tailed class I-binding peptides bind to CpG adjuvant and enhance primary CTL responses. J Immunol 175:3681-9
Lanza, Robert P; Chung, Ho Yun; Yoo, James J et al. (2002) Generation of histocompatible tissues using nuclear transplantation. Nat Biotechnol 20:689-96
Nevala, W K; Paul, C; Wettstein, P J (1998) Immunodominant minor histocompatibility antigen peptides recognized by cytolytic T lymphocytes primed by indirect presentation. Transplantation 65:559-69
Strausbauch, M A; Nevala, W K; Roopenian, D C et al. (1998) Identification of mimotopes for the H4 minor histocompatibility antigen. Int Immunol 10:421-34
Borson, N D; Strausbauch, M A; Wettstein, P J et al. (1998) Direct quantitation of RNA transcripts by competitive single-tube RT-PCR and capillary electrophoresis. Biotechniques 25:130-7
Johnston, S L; Graham, D; Wettstein, P J (1997) Diversity of alpha and beta subunits of T-cell receptors specific for the H4 minor histocompatibility antigen. Immunogenetics 46:17-28
Nevala, W K; Wettstein, P J (1997) Immunodominant minor histocompatibility antigen peptides presented by H2Db molecules. Transplantation 64:1323-30
Nevala, W K; Paul, C; Wettstein, P J (1997) Reduced diversity of CTLs specific for multiple minor histocompatibility antigens relative to allograft rejection in vivo. J Immunol 158:1102-7

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