Characterization and manipulation of T cell immunity to skin grafts expressing a transgenic minor antigen.
BACKGROUND
Minor histocompatibility antigens play a significant role in allograft rejection when donor and recipient are matched at MHC loci. An improved understanding of T cell immunity directed toward a model minor antigen may provide new approaches for preventing graft rejection.


METHODS
C57BL/6 (B6) recipient mice were engrafted with skin from B6 beta-galactosidase transgenic (beta-gal tg) donors and the induced T cell immune responses were characterized by cytokine ELISA spot assay. beta-gal-specific immunity was manipulated prior to transplant through preinjection with beta-gal in complete Freund's adjuvant (CFA) or through preinjection with soluble beta-gal i.v.


RESULTS
B6 mice rejected beta-gal tg skin by day 25. Rejection was associated with a low frequency of predominantly CD8+, interferon-gamma-producing T cells capable of directly recognizing both beta-gal tg cells and an immunodominant major histocompatibility complex I-restricted peptide derived from the beta-gal protein. Rejection of multiple minor antigen disparate skin and major histocompatibility complex-disparate skin occurred significantly faster, and was associated with a 10- to 30-fold higher frequency of alloreactive T cells, than rejection of beta-gal tg skin. Prepriming of recipients with beta-gal in complete Freund's adjuvant resulted in an increased frequency of beta-gal-specific T cells and accelerated rejection of beta-gal tg skin. Intravenous injection of soluble beta-gal-induced graft tolerance and a lack of detectable beta-gal-specific immunity.


CONCLUSIONS
The findings reveal that transgenically expressed beta-gal behaves as a minor transplantation antigen and that manipulation of the beta-gal-specific T cell repertoire can dramatically affect rejection of beta-gal tg skin grafts. The work provides the foundation for mechanistic studies of tolerogenesis to minor antigenic determinants.
Valujskikh
A
A
Department of Medicine, Louis Stokes Cleveland Veterans Affairs Medical Center, Institute of Pathology, Case Western Reserve University, Ohio 44106, USA.
Matesic
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D
Heeger
P S
PS
D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D000939:Epitopes / Q000276:immunology; D005260:Female; D006084:Graft Rejection / Q000276:immunology; D007108:Immune Tolerance / Q000235:genetics; D007371:Interferon-gamma / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D015778:Minor Histocompatibility Antigens / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology*; D016038:Skin Transplantation / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D018417:Th1 Cells / Q000378:metabolism; D019076:Transgenes / Q000276:immunology; D001616:beta-Galactosidase / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology*
D016207:Cytokines; D000939:Epitopes; D015778:Minor Histocompatibility Antigens; D007371:Interferon-gamma; D001616:beta-Galactosidase