Role of intrathymic rat class II+ cells in maintaining deletional tolerance in xenogeneic rat-->mouse bone marrow chimeras

Transplantation. 1998 May 15;65(9):1216-24. doi: 10.1097/00007890-199805150-00013.

Abstract

Background: Mixed xenogeneic bone marrow chimerism and tolerance can be induced in mice conditioned with a nonmyeloablative regimen followed by injection of T cell-depleted rat bone marrow cells. We hypothesized that, despite a gradual decline in rat hematopoiesis observed in these chimeras, as long as rat class II+ antigen-presenting cells remain in their thymi, tolerance will persist as a result of deletion of donor-reactive thymocytes.

Methods: The level of chimerism and of mouse Vbeta5 and Vbeta11 T-cell deletion was followed over time. These results were correlated with the presence of rat class II+ cells in the thymus by immunohistochemistry and the presence of tolerance in long-term chimeras by in vivo and in vitro assays.

Results: (1) Proliferation and cytotoxicity assays, as well as skin graft survival, demonstrated the presence of specific tolerance to host and to donor rat, with normal reactivity to third-party rat and mouse stimulators, even as late as 85 weeks after bone marrow transplantation. (2) The absence of mature Vbeta5+ and Vbeta11+ host T cells in the thymus and periphery was always associated with the presence of rat class II+ cells in the thymus, and incomplete deletion of T cells expressing these Vbeta families was observed in thymi in which rat class II+ cells were not detectable.

Conclusions: Donor-specific T-cell tolerance is maintained during the period when donor-type reconstitution declines, and is most likely mediated by intrathymic clonal deletion of T cells that recognize antigens expressed on class II+ rat cells.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Bone Marrow / physiology*
  • Bone Marrow Transplantation*
  • Chimera / genetics*
  • Chimera / physiology
  • Clonal Deletion / physiology*
  • Female
  • Histocompatibility Antigens Class II / analysis*
  • Immune Tolerance / genetics*
  • Mice
  • Mice, Inbred Strains
  • Rats
  • Rats, Inbred Strains
  • Receptors, Antigen, T-Cell, alpha-beta / metabolism
  • T-Lymphocytes / metabolism
  • Thymus Gland / cytology
  • Thymus Gland / immunology*
  • Thymus Gland / physiology*
  • Transplantation, Heterologous*

Substances

  • Histocompatibility Antigens Class II
  • Receptors, Antigen, T-Cell, alpha-beta