TGFβ-dependent expression of PD-1 and PD-L1 controls CD8+ T cell anergy in transplant tolerance
Marije Baas,
Alix Besançon,
Tania Goncalves,
Fabrice Valette,
Hideo Yagita,
Birgit Sawitzki,
Hans-Dieter Volk,
Emmanuelle Waeckel-Enée,
Benedita Rocha,
Lucienne Chatenoud,
Sylvaine You
Affiliations
Marije Baas
University Paris Descartes, Sorbonne Paris Cité, Paris, France; Institut National de la Santé et de la Recherche Médicale Unit 1151, Institut Necker-Enfants Malades, Paris, France; Centre National de la Recherche Scientifique UMR 8253, Institut Necker-Enfants Malades, Paris, France
Alix Besançon
University Paris Descartes, Sorbonne Paris Cité, Paris, France; Institut National de la Santé et de la Recherche Médicale Unit 1151, Institut Necker-Enfants Malades, Paris, France; Centre National de la Recherche Scientifique UMR 8253, Institut Necker-Enfants Malades, Paris, France
Tania Goncalves
University Paris Descartes, Sorbonne Paris Cité, Paris, France; Institut National de la Santé et de la Recherche Médicale Unit 1151, Institut Necker-Enfants Malades, Paris, France; Centre National de la Recherche Scientifique UMR 8253, Institut Necker-Enfants Malades, Paris, France
Fabrice Valette
University Paris Descartes, Sorbonne Paris Cité, Paris, France; Institut National de la Santé et de la Recherche Médicale Unit 1151, Institut Necker-Enfants Malades, Paris, France; Centre National de la Recherche Scientifique UMR 8253, Institut Necker-Enfants Malades, Paris, France
Hideo Yagita
Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan
Birgit Sawitzki
Institute of Medical Immunology, Charité University Medicine, Berlin, Germany
Hans-Dieter Volk
Institute of Medical Immunology, Charité University Medicine, Berlin, Germany; Berlin-Brandenburg Center for Regenerative Therapies, Charité University Medicine, Berlin, Germany
Emmanuelle Waeckel-Enée
University Paris Descartes, Sorbonne Paris Cité, Paris, France; Institut National de la Santé et de la Recherche Médicale Unit 1151, Institut Necker-Enfants Malades, Paris, France; Centre National de la Recherche Scientifique UMR 8253, Institut Necker-Enfants Malades, Paris, France
Benedita Rocha
University Paris Descartes, Sorbonne Paris Cité, Paris, France; Lymphocyte Population Biology Unit, Pasteur Institute, Paris, France
Lucienne Chatenoud
University Paris Descartes, Sorbonne Paris Cité, Paris, France; Institut National de la Santé et de la Recherche Médicale Unit 1151, Institut Necker-Enfants Malades, Paris, France; Centre National de la Recherche Scientifique UMR 8253, Institut Necker-Enfants Malades, Paris, France
Sylvaine You
University Paris Descartes, Sorbonne Paris Cité, Paris, France; Institut National de la Santé et de la Recherche Médicale Unit 1151, Institut Necker-Enfants Malades, Paris, France; Centre National de la Recherche Scientifique UMR 8253, Institut Necker-Enfants Malades, Paris, France
CD8+ T cell anergy is a critical mechanism of peripheral tolerance, poorly investigated in response to immunotherapy. Here, using a pancreatic islet allograft model and CD3 antibody therapy, we showed, by single cell gene profiling, that intragraft CD8+ lymphocytes coexpressing granzyme B and perforin were selectively depleted through the Fas/FasL pathway. This step led to long-standing anergy of the remaining CD8+ T cells marked by the absence of cytotoxic/inflammatory gene expression also confirmed by transcriptome analysis. This sustained unresponsiveness required the presence of the alloantigens. Furthermore, tissue-resident CD8+ lymphocytes produced TGFβ and expressed the inhibitory receptors PD-1 and PD-L1. Blockade of TGFβ downregulated PD-1 and PD-L1 expression and precipitated graft rejection. Neutralizing PD-1, PD-L1 or TGFβRII signaling in T cells also abrogated CD3 antibody-induced tolerance. These studies unravel novel mechanisms underlying CD8+ T cell anergy and reveal a cell intrinsic regulatory link between the TGFβ and the PD-1/PD-L1 pathways.
