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

Besançon, Alix, MD, PhD1,2,3; Demir, Zeynep, MD1,2,3; Goncalves, Tania1,2,3; Valette, Fabrice1,2,3; Panafieu, Emilie1,2,3; Chatenoud, Lucienne, MD, PhD1,2,3; You, Sylvaine, PhD1,2,3

doi: 10.1097/TP.0000000000002261
Original Basic Science—General

Background T cell–mediated graft rejection is mostly correlated with potent Th1 responses. However, because 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 tumor necrosis factor tumor necrosis factor α 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 tumor necrosis factor α–mediated but not IL-4 nor IL-17–mediated allogeneic responses.

Conclusions 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 refine the therapeutic/immunosuppressive regimens applied in diabetic patients receiving islets or pancreas allografts.

Besançon et al report that T-bet-deficient recipients spontaneously accept allogeneic pancreatic islets, whereas IFNγ-deficient recipients retain their ability to reject due to expression of compensatory effector mechanisms comprising increased Eomes, cytolytic molecules, and TNFα.

1 University Paris Descartes, Sorbonne Paris Cité, Paris, France.

2 INSERM U1151, Institut Necker-Enfants Malades, Paris, France.

3 CNRS UMR 8253, Institut Necker-Enfants Malades, Paris, France.

Received 20 December 2017. Revision received 2 March 2018.

Accepted 20 March 2018.

Present address for S.Y.: INSERM U1016, Institut Cochin, 75014 Paris, France.

A.B. and Z.D. equally contributed to this work.

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).

The authors declare no conflicts of interest.

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 article. S. Y. designed and directed the study, analyzed the data and wrote the article.

Correspondence: Sylvaine You, PhD, INSERM U1016, Institut Cochin, Bâtiment Cassini, 123 Bd de Port Royal, 75014 Paris, France. (sylvaine.you@inserm.fr).

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