Allospecific Rejection of MHC Class I-Deficient Bone Marrow by CD8 T Cells

作者：Haspot F; Li H W; Lucas C L; Fehr T; Beyaz S; Sykes M^*

来源：American Journal of Transplantation, 2014, 14(1): 49-58.

DOI：10.1111/ajt.12525

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

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 (3Gy 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.
In a nonmyeloablative mouse bone marrow transplant model, the authors observe that recipient CD8 T cells specifically reject allogeneic, but not syngeneic, marrow lacking MHC class I heavy or light chains, in a manner that implicates indirect allorecognition through a TCR-independent recognition pathway.

• 出版日期2014-1