Alloreactive T lymphocytes can respond to intact foreign MHC presented on allogeneic antigen presenting cells (APC), through the direct pathway and can also recognize allopeptides presented in the context of self-MHC, through the indirect pathway. It is not known to what extend these two pathways play a role in the graft rejection. Only a comparative T cell repertoire analysis of these two pathways will result in a better understanding. We performed such analysis using HLA-DR1 and DR4 transgenic (tg) mice that differ only for that alloantigen. While DR1 and DR4 molecules have the same TCR contact surfaces, the DR1 tg mice initiate a strong anti-DR4 alloresponse in an MLC. We decided to split this alloresponse into direct and indirect pathways, by developing in vitro DR l anti-DR4 T cell lines. A higher number of T cell clones (26) were found in the direct pathway compared to the indirect (8). Surprisingly, 3 of these clonotypes were present in both direct and indirect repertoires. Two of the shared clonotypes were also public as they were found in different mice. The same in vitro public clonotypes were observed in vivo after injection of DR4 tg splenocytes into a DR1 tg mouse. These data suggest that mismatched MHC molecules with polymorphisms only in the peptide binding groove can be recognized by the same T cells if they bind the same peptide. Therefore, in our model, the same DRl-selected T cells can recognize a DR4derived peptide whether it is presented by DR1 or DR4. It is a general assumption that the definition of direct and indirect alloreresponses is based on the origin of the APCs (donor or host) involved in T cell activation. However our data suggest that the location of polymorphisms is important for the classification of direct or indirect alloreactive T cells. These findings may have important implications for understanding the relative contribution of direct and indirect alloreactivities in the graft rejection and for designing selective immunotherapy in allotransplantation.
|Issue number||11 PART I|
|Publication status||Published - 2000|
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