Characterization of the autoreactive T cell repertoire in cyclosporin- induced syngeneic graft-versus-host disease: A highly conserved repertoire mediates autoaggression

A. C. Fischer, P. P. Ruvolo, R. Burt, L. R. Horwitz, E. C. Bright, J. M. Hess, W. E. Beschorner, A. D. Hess

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Abstract

Syngeneic graft-vs-host disease (SGVHD) is a MHC class II-restricted T cell-mediated autoimmune syndrome that occurs following syngeneic bone marrow transplantation and the administration of cyclosporin (CsA). The present studies evaluated the Vβ repertoire of T lymphocytes that mediate SGVHD. To facilitate analysis, SGVHD effector cells were adoptively transferred into thymectomized syngeneic recipients reconstituted with T cell-depleted bone marrow to provide an environment that allows for the selective clonal expansion of autoreactive T cells. Analysis of target tissues and PBL by reverse transcriptase PCR using oligonucleotide Vβ-specific primers revealed a predominance of Vβ8.5+ T cells and a minor population expressing Vβ10. The majority of infiltrating lymphocytes in target tissues was confirmed to be Vβ8.5+ by in situ hybridization and by immunoperoxidase staining. A small population of Vβ10+ cells could also be detected. Furthermore, SGVHD effector T splenocytes depleted of lymphocytes expressing either the TCR- αβ3 or the Vβ8.5 determinant could not adoptively transfer SGVHD. Depletion of T cells expressing the Vβ10 determinant delayed the onset of this autoaggression syndrome. Subset analysis of the autoreactive T cell compartment revealed that the Vβ8.5 determinant was expressed on both CD4+ and CD8+ lymphocytes whereas the Vβ10 determinant was principally expressed on a minor population of CD4+ autoreactive T cells. These data were confirmed by limiting dilution analysis. Additional studies examining the effect of CsA on thymic differentiation revealed that although Vβ8.5 is not normally clonally deleted, there was a pronounced shift in the expression of this determinant between CD4 and CD8 single positive thymocytes, suggesting that CsA may inhibit normal positive selection processes for MHC class I and class II reactive T cells.

Original languageEnglish (US)
Pages (from-to)3713-3725
Number of pages13
JournalJournal of Immunology
Volume154
Issue number8
StatePublished - Jan 1 1995

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Fischer, A. C., Ruvolo, P. P., Burt, R., Horwitz, L. R., Bright, E. C., Hess, J. M., Beschorner, W. E., & Hess, A. D. (1995). Characterization of the autoreactive T cell repertoire in cyclosporin- induced syngeneic graft-versus-host disease: A highly conserved repertoire mediates autoaggression. Journal of Immunology, 154(8), 3713-3725.