title: TGFβ-dependent expression of PD-1 and PD-L1 controls CD8(+) T cell anergy in transplant tolerance.
abstract: 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.
authors.affiliation: 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.
authors.forename: Marije
authors.initials: M
authors.lastname: Baas
authors.affiliation: 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.
authors.forename: Alix
authors.initials: A
authors.lastname: Besançon
authors.affiliation: 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.
authors.forename: Tania
authors.initials: T
authors.lastname: Goncalves
authors.affiliation: 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.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Valette
authors.affiliation: Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.affiliation: Institute of Medical Immunology, Charité University Medicine, Berlin, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Sawitzki
authors.affiliation: Institute of Medical Immunology, Charité University Medicine, Berlin, Germany.|Berlin-Brandenburg Center for Regenerative Therapies, Charité University Medicine, Berlin, Germany.
authors.forename: Hans-Dieter
authors.initials: HD
authors.lastname: Volk
authors.affiliation: 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.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Waeckel-Enée
authors.affiliation: University Paris Descartes, Sorbonne Paris Cité, Paris, France.|Lymphocyte Population Biology Unit, Pasteur Institute, Paris, France.
authors.forename: Benedita
authors.initials: B
authors.lastname: Rocha
authors.affiliation: 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.
authors.forename: Lucienne
authors.initials: L
authors.lastname: Chatenoud
authors.affiliation: 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.
authors.forename: Sylvaine
authors.initials: S
authors.lastname: You
mesh_terms: D064591:Allografts / Q000276:immunology; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage; D060890:B7-H1 Antigen / Q000096:biosynthesis*; D017252:CD3 Complex / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D017635:Clonal Anergy; D007108:Immune Tolerance; D007515:Islets of Langerhans / Q000276:immunology; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D061026:Programmed Cell Death 1 Receptor / Q000096:biosynthesis*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014180:Transplantation
chemical_list: D000906:Antibodies; D060890:B7-H1 Antigen; D017252:CD3 Complex; C498919:Cd274 protein, mouse; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D016212:Transforming Growth Factor beta
keywords: CD8+ T cells; PD-1/PD-L1; TGF-beta; anergy; immunology; mouse; tolerance; tranplantation
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