title: The transcription factor NFAT promotes exhaustion of activated CD8⁺ T cells.
abstract: During persistent antigen stimulation, CD8(+) T cells show a gradual decrease in effector function, referred to as exhaustion, which impairs responses in the setting of tumors and infections. Here we demonstrate that the transcription factor NFAT controls the program of T cell exhaustion. When expressed in cells, an engineered form of NFAT1 unable to interact with AP-1 transcription factors diminished T cell receptor (TCR) signaling, increased the expression of inhibitory cell surface receptors, and interfered with the ability of CD8(+) T cells to protect against Listeria infection and attenuate tumor growth in vivo. We defined the genomic regions occupied by endogenous and engineered NFAT1 in primary CD8(+) T cells and showed that genes directly induced by the engineered NFAT1 overlapped with genes expressed in exhausted CD8(+) T cells in vivo. Our data show that NFAT promotes T cell anergy and exhaustion by binding at sites that do not require cooperation with AP-1.
authors: Department of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
authors: Gustavo J
authors: GJ
authors: Martinez
authors: Department of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
authors: Renata M
authors: RM
authors: Pereira
authors: Department of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA; Department of Information and Computer Science, Aalto University School of Science, Aalto 00076, Finland.
authors: Tarmo
authors: T
authors: Äijö
authors: Division of Rheumatology, Allergy, and Immunology, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors: Edward Y
authors: EY
authors: Kim
authors: Division of Rheumatology, Allergy, and Immunology, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors: Francesco
authors: F
authors: Marangoni
authors: Department of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA; Department of Cancer Biology, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors: Matthew E
authors: ME
authors: Pipkin
authors: Department of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
authors: Susan
authors: S
authors: Togher
authors: Institute of Molecular Immunology, Helmholtz Zentrum München, Marchioninistrasse 25, 81377 Munich, Germany; Ludwig-Maximilians-Universität München, Institute for Immunology, Goethestrasse 31, 80336 Munich, Germany.
authors: Vigo
authors: V
authors: Heissmeyer
authors: Department of Radiology, St Lukes Roosevelt Hospital Center, New York, NY 10019, USA.
authors: Yi Chen
authors: YC
authors: Zhang
authors: Department of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
authors: Shane
authors: S
authors: Crotty
authors: Immune Disease Institute, Harvard Medical School and Program in Cellular and Molecular Medicine, Children's Hospital Boston, Boston, MA 02115, USA.
authors: Edward D
authors: ED
authors: Lamperti
authors: Department of Microbiology and Immunology, Sandler Asthma Basic Research Center, University of California, San Francisco, San Francisco, CA 94143, USA.
authors: K Mark
authors: KM
authors: Ansel
authors: Division of Rheumatology, Allergy, and Immunology, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors: Thorsten R
authors: TR
authors: Mempel
authors: Department of Information and Computer Science, Aalto University School of Science, Aalto 00076, Finland. Electronic address: harri.lahdesmaki@aalto.fi.
authors: Harri
authors: H
authors: Lähdesmäki
authors: Department of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
authors: Patrick G
authors: PG
authors: Hogan
authors: Department of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA. Electronic address: arao@liai.org.
authors: Anjana
authors: A
authors: Rao
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D017635:Clonal Anergy / Q000187:drug effects / Q000235:genetics*; D005786:Gene Expression Regulation / Q000235:genetics; D008089:Listeria monocytogenes / Q000276:immunology; D008088:Listeriosis / Q000276:immunology / Q000382:microbiology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D050778:NFATC Transcription Factors / Q000235:genetics / Q000502:physiology*; D009369:Neoplasms / Q000276:immunology; D011401:Promoter Regions, Genetic / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D011994:Recombinant Proteins / Q000235:genetics / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000378:metabolism*
chemical_list: D050778:NFATC Transcription Factors; C494007:Nfatc2 protein, mouse; D011948:Receptors, Antigen, T-Cell; D011994:Recombinant Proteins; D018808:Transcription Factor AP-1