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Am J Transplant. 2014 Jan;14(1):49-58. doi: 10.1111/ajt.12525. Epub 2013 Dec 4.

Allospecific rejection of MHC class I-deficient bone marrow by CD8 T cells.

Author information

1
Department of Surgery, Transplantation Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA.

Abstract

Avoidance of long-term immunosuppression is a desired goal in organ transplantation. Mixed chimerism offers a promising approach to tolerance induction, and we have aimed to develop low-toxicity, nonimmunodepleting approaches to achieve this outcome. In a mouse model achieving fully MHC-mismatched allogeneic bone marrow engraftment with minimal conditioning (3 Gy total body irradiation followed by anti-CD154 and T cell-depleted allogeneic bone marrow cells), CD4 T cells in the recipient are required to promote tolerance of preexisting alloreactive recipient CD8 T cells and thereby permit chimerism induction. We now demonstrate that mice devoid of CD4 T cells and NK cells reject MHC Class I-deficient and Class I/Class II-deficient marrow in a CD8 T cell-dependent manner. This rejection is specific for donor alloantigens, since recipient hematopoiesis is not affected by donor marrow rejection and MHC Class I-deficient bone marrow that is syngeneic to the recipient is not rejected. Recipient CD8 T cells are activated and develop cytotoxicity against MHC Class I-deficient donor cells in association with rejection. These data implicate a novel CD8 T cell-dependent bone marrow rejection pathway, wherein recipient CD8 T cells indirectly activated by donor alloantigens promote direct killing, in a T cell receptor-independent manner, of Class I-deficient donor cells.

KEYWORDS:

Bone marrow transplantation; CD8 T cells; indirect alloreactivity; tolerance

PMID:
24304495
PMCID:
PMC4045013
DOI:
10.1111/ajt.12525
[Indexed for MEDLINE]
Free PMC Article

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