Differential Impact of T-bet and IFN on Pancreatic Islet Allograft Rejection

Background T cell-mediated graft rejection is mostly correlated with potent Th1 responses. However, because IFN-/- mice reject their graft as efficiently as wild-type (WT) mice, the exact contribution of IFN and its transcription factor T-bet remains a matter of debate. Here, we address this question in the context of pancreatic islet allograft to better inform the molecular pathways that hampers islet survival in vivo. Methods Pancreatic islets from BALB/c mice were transplanted in WT, IFN-/-, or T-bet(-/-) C57BL/6 mice. Graft survival and the induction of effector and cytotoxic T-cell responses were monitored. Results Rejection of fully mismatched islet allografts correlated with high expression of both IFN and T-bet in WT recipients. However, allogeneic islets were permanently accepted in T-bet(-/-) mice, in contrast to IFN-/- hosts. Long-term survival correlated with decreased CD4(+) and CD8(+) T-cell infiltrates, drastically reduced donor-specific IFN and tumor necrosis factor tumor necrosis factor responses and very low expression of the cytotoxic markers granzyme B, perforin, and FasLigand. In addition, in vitro and in vivo data pointed to an increased susceptibility of T-bet(-/-) CD8(+) T cell to apoptosis. These observations were not reported in IFN-/- mice, which have set up compensatory effector mechanisms comprising an increased expression of the transcription factor Eomes and cytolytic molecules as well as tumor necrosis factor -mediated but not IL-4 nor IL-17-mediated allogeneic responses. Conclusions Anti-islet T-cell responses require T-bet but not IFN-dependent programs. Our results provide new clues on the mechanisms dictating islet rejection and may help refine the therapeutic/immunosuppressive regimens applied in diabetic patients receiving islets or pancreas allografts.