Differential impact of T-bet and IFNγ on pancreatic islet allograft rejection

Background T-cell-mediated graft rejection is mostly correlated with potent Th1 responses. However, since IFNγ-/- mice reject their graft as efficiently as wild-type (WT) mice, the exact contribution of IFNγ 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, IFNγ-/- 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 IFNγ and T-bet in WT recipients. However, allogeneic islets were permanently accepted in T-bet-/- mice, in contrast to IFNγ-/- hosts. Long-term survival correlated with decreased CD4+ and CD8+ T cell infiltrates, drastically reduced donor-specific IFNγ and TNFα 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 IFNγ-/- mice, which have set up compensatory effector mechanisms comprising an increased expression of the transcription factor Eomes and cytolytic molecules as well as TNFα- but not IL-4 nor IL-17-mediated allogeneic responses. Conclusion Anti-islet T cell responses require T-bet but not IFNγ-dependent programs. Our results provide new clues on the mechanisms dictating islet rejection and may help refining the therapeutic/immunosuppressive regimens applied in diabetic patients receiving islets or pancreas allografts. *These authors equally contributed to this work. Corresponding author: Dr. Sylvaine You, INSERM U1016 – Institut Cochin, Bâtiment Cassini, 123 Bd de Port Royal, 75014 Paris, France. E-mail: sylvaine.you@inserm.fr Authorship A.B and Z.D. designed experiments, performed experiments, analyzed and interpreted the data. T.G, F.V. and E.P. performed experiments and analyzed the data. L.C. provided critical advice and help in writing the manuscript. S. Y. designed and directed the study, analyzed the data and wrote the manuscript. Disclosure The authors declare no conflicts of interest. Funding: This work was supported by grants from the RISET consortium (Reprogramming the Immune System for the Establishment of Tolerance) from the European Commission (FP6), Institutional funding from INSERM and University Paris Descartes, the Fondation CENTAURE, and the Fondation DAY SOLVAY. A. Besançon was supported by a doctoral fellowship from INSERM by a price from the Société Française d'Endocrinologie et Diabétologie Pédiatrique (SFEDP, grant from NOVONORDISK). Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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