title: The tumor necrosis factor alpha-induced protein 3 (TNFAIP3, A20) imposes a brake on antitumor activity of CD8 T cells.
abstract: The transcription factor NF-κB is central to inflammatory signaling and activation of innate and adaptive immune responses. Activation of the NF-κB pathway is tightly controlled by several negative feedback mechanisms, including A20, an ubiquitin-modifying enzyme encoded by the tnfaip3 gene. Mice with selective deletion of A20 in myeloid, dendritic, or B cells recapitulate some human inflammatory pathology. As we observed high expression of A20 transcripts in dysfunctional CD8 T cells in an autochthonous melanoma, we analyzed the role of A20 in regulation of CD8 T-cell functions, using mice in which A20 was selectively deleted in mature conventional T cells. These mice developed lymphadenopathy and some organ infiltration by T cells but no splenomegaly and no detectable pathology. A20-deleted CD8 T cells had increased sensitivity to antigen stimulation with production of large amounts of IL-2 and IFNγ, correlated with sustained nuclear expression of NF-κB components reticuloendotheliosis oncogene c-Rel and p65. Overexpression of A20 by retroviral transduction of CD8 T cells dampened their intratumor accumulation and antitumor activity. In contrast, relief from the A20 brake in NF-κB activation in adoptively transferred antitumor CD8 T cells led to improved control of melanoma growth. Tumor-infiltrating A20-deleted CD8 T cells had enhanced production of IFNγ and TNFα and reduced expression of the inhibitory receptor programmed cell death 1. As manipulation of A20 expression in CD8 T cells did not result in pathologic manifestations in the mice, we propose it as a candidate to be targeted to increase antitumor efficiency of adoptive T-cell immunotherapy.
authors.affiliation: Centre d'Immunologie de Marseille-Luminy, Aix-Marseille University (UM 2), Case 906, 13288 Marseille Cedex 9, France;Institut National de la Santé et de la Recherche Médicale, U1104, 13288 Marseille, France;Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7280, 13288 Marseille, France;
authors.forename: Marilyn
authors.initials: M
authors.lastname: Giordano
authors.affiliation: Centre d'Immunologie de Marseille-Luminy, Aix-Marseille University (UM 2), Case 906, 13288 Marseille Cedex 9, France;Institut National de la Santé et de la Recherche Médicale, U1104, 13288 Marseille, France;Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7280, 13288 Marseille, France;
authors.forename: Romain
authors.initials: R
authors.lastname: Roncagalli
authors.affiliation: Centre d'Immunologie de Marseille-Luminy, Aix-Marseille University (UM 2), Case 906, 13288 Marseille Cedex 9, France;Institut National de la Santé et de la Recherche Médicale, U1104, 13288 Marseille, France;Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7280, 13288 Marseille, France;
authors.forename: Pierre
authors.initials: P
authors.lastname: Bourdely
authors.affiliation: Centre d'Immunologie de Marseille-Luminy, Aix-Marseille University (UM 2), Case 906, 13288 Marseille Cedex 9, France;Institut National de la Santé et de la Recherche Médicale, U1104, 13288 Marseille, France;Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7280, 13288 Marseille, France;
authors.forename: Lionel
authors.initials: L
authors.lastname: Chasson
authors.affiliation: Centre d'Immunologie de Marseille-Luminy, Aix-Marseille University (UM 2), Case 906, 13288 Marseille Cedex 9, France;Institut National de la Santé et de la Recherche Médicale, U1104, 13288 Marseille, France;Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7280, 13288 Marseille, France;
authors.forename: Michel
authors.initials: M
authors.lastname: Buferne
authors.affiliation: Division of Molecular Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan;
authors.forename: Sho
authors.initials: S
authors.lastname: Yamasaki
authors.affiliation: Department of Biomedical Molecular Biology, Ghent University, B-9052 Ghent, Belgium; andInflammation Research Center, Vlaams Instituut voor Biotechnologie, B-9052 Ghent, Belgium.
authors.forename: Rudi
authors.initials: R
authors.lastname: Beyaert
authors.affiliation: Department of Biomedical Molecular Biology, Ghent University, B-9052 Ghent, Belgium; andInflammation Research Center, Vlaams Instituut voor Biotechnologie, B-9052 Ghent, Belgium.
authors.forename: Geert
authors.initials: G
authors.lastname: van Loo
authors.affiliation: Centre d'Immunologie de Marseille-Luminy, Aix-Marseille University (UM 2), Case 906, 13288 Marseille Cedex 9, France;Institut National de la Santé et de la Recherche Médicale, U1104, 13288 Marseille, France;Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7280, 13288 Marseille, France;
authors.forename: Nathalie
authors.initials: N
authors.lastname: Auphan-Anezin
authors.affiliation: Centre d'Immunologie de Marseille-Luminy, Aix-Marseille University (UM 2), Case 906, 13288 Marseille Cedex 9, France;Institut National de la Santé et de la Recherche Médicale, U1104, 13288 Marseille, France;Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7280, 13288 Marseille, France;
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Schmitt-Verhulst
authors.affiliation: Centre d'Immunologie de Marseille-Luminy, Aix-Marseille University (UM 2), Case 906, 13288 Marseille Cedex 9, France;Institut National de la Santé et de la Recherche Médicale, U1104, 13288 Marseille, France;Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7280, 13288 Marseille, France; verdeil@ciml.univ-mrs.fr.
authors.forename: Grégory
authors.initials: G
authors.lastname: Verdeil
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007111:Immunity, Cellular; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology*; D008545:Melanoma / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology
chemical_list: D000951:Antigens, Neoplasm; D007376:Interleukin-2; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D003546:Cysteine Endopeptidases; C513261:Tnfaip3 protein, mouse
keywords: T-cell activation; inflammation; tumor immunity