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Immunity. 2015 Feb 17;42(2):265-278. doi: 10.1016/j.immuni.2015.01.006. Epub 2015 Feb 10.

The transcription factor NFAT promotes exhaustion of activated CD8⁺ T cells.

Author information

1
Department of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
2
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.
3
Division of Rheumatology, Allergy, and Immunology, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
4
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.
5
Institute of Molecular Immunology, Helmholtz Zentrum München, Marchioninistrasse 25, 81377 Munich, Germany; Ludwig-Maximilians-Universität München, Institute for Immunology, Goethestrasse 31, 80336 Munich, Germany.
6
Department of Radiology, St Lukes Roosevelt Hospital Center, New York, NY 10019, USA.
7
Department of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
8
Immune Disease Institute, Harvard Medical School and Program in Cellular and Molecular Medicine, Children's Hospital Boston, Boston, MA 02115, USA.
9
Department of Microbiology and Immunology, Sandler Asthma Basic Research Center, University of California, San Francisco, San Francisco, CA 94143, USA.
10
Department of Information and Computer Science, Aalto University School of Science, Aalto 00076, Finland. Electronic address: harri.lahdesmaki@aalto.fi.
11
Department of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA. Electronic address: arao@liai.org.

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.

PMID:
25680272
PMCID:
PMC4346317
DOI:
10.1016/j.immuni.2015.01.006
[Indexed for MEDLINE]
Free PMC Article

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