Date: Sunday, May 3, 2015
Session Time: 4:00pm-5:30pm
Presentation Time: 4:36pm-4:48pm
Location: Room 120-ABC
Although there is increasing evidence that recipient DCs can acquire intact MHC class I by trogocytosis from parenchymal cells, the functional relevance of the 'semi-direct' antigen presentation to CD8 T cells that this permits, to allograft rejection, has not been previously demonstrated.
Murine heterotopic cardiac transplant models were utilised. Balbc donors were lethally irradiated to eradicate haematopoietic cells (HPC) (Balb/cHPC-), such that parenchymal cells were the only source of alloantigen. Recipients included: 1) 2C transgenic mice (monoclonal population of CD8 T cells against Ld MHC class I); 2) Splenectomised aly/aly (aly/alyspl) mice, to investigate the importance of secondary lymphoid tissue (SLT); 3) CD11c-DTR transgenic mice, in which host DCs can be selectively depleted by treatment with diphtheria toxin. Recipient CD4 T cells and B cells were depleted with monoclonal antibodies.
Results 2C transgenic mice rejected Balb/cHPC- grafts as rapidly as non-irradiated Balb/c grafts (MST = 5d vs. 4d respectively; p=0.4) suggesting an effective mechanism for parenchymal cell driven CD8 T cell mediated rejection. Balb/cHPC- allografts showed prolonged survival (>50d) in aly/alyspl mice given 2C CD8 T cells whereas in non-splenectomised controls all grafts rejected (MST = 17d; p=0.01). In addition, when aly/alyspl mice were given activated 2C CD8 T cells (from a 2C recipient of a Balb/c cardiac graft) they rapidly rejected Balb/cHPC- allografts (MST = 7d; p=0.01) suggesting an essential role for SLT in this pathway. Wildtype recipient CD8 T alloreactivity acutely rejected Balb/cHPC- allografts in CD11c-DTR recipients lacking B cells, with rejection significantly attenuated if either CD4 T cells, or DCs were additionally depleted (MST = 12 vs >50 and 26 respectively; p<0.01), highlighting an essential role for both recipient DCs and CD4 T cells in driving CD8 alloreactivity.
These results provide support for the semi-direct pathway of allorecognition having the potential to contribute to allograft rejection. Recipient DCs can acquire intact MHC class I from donor parenchymal cells, and upon transit to SLT, receive indirect CD4 T cell help to activate directly alloreactive CD8 T cells.
To cite this abstract in AMA style:Ali J, Harper S, Negus M, Bolton E, Bradley J, Pettigrew G. Cytotoxic CD8 T Cell Recognition of Acquired, Intact MHC Alloantigen On Host Dendritic Cells Promotes Acute Allograft Rejection [abstract]. Am J Transplant. 2015; 15 (suppl 3). https://atcmeetingabstracts.com/abstract/cytotoxic-cd8-t-cell-recognition-of-acquired-intact-mhc-alloantigen-on-host-dendritic-cells-promotes-acute-allograft-rejection/. Accessed June 12, 2021.
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