Introduction

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.

Methods

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.

Conclusion:

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.

« Back to 2015 American Transplant Congress