The Transcription Factor NFAT Promotes Exhaustion of Activated CD8+ T Cells
| Autor: | Patrick G. Hogan, Shane Crotty, Anjana Rao, Vigo Heissmeyer, Susan Togher, Matthew E. Pipkin, K. Mark Ansel, Francesco Marangoni, Edward Y. Kim, Thorsten R. Mempel, Edward D. Lamperti, Harri Lähdesmäki, Tarmo Äijö, Gustavo J. Martinez, Renata M. Pereira, Yi Chen Zhang |
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| Rok vydání: | 2015 |
| Předmět: |
T cell
Cells Immunology Receptors Antigen T-Cell Mice Transgenic Biology CD8-Positive T-Lymphocytes Lymphocyte Activation Article Transgenic Promoter Regions Mice Antigen Genetic Neoplasms Receptors medicine Genetics Cytotoxic T cell Animals 2.1 Biological and endogenous factors Immunology and Allergy Listeriosis Aetiology Receptor Promoter Regions Genetic Transcription factor Cells Cultured Cancer Clonal Anergy Cultured NFATC Transcription Factors 5.2 Cellular and gene therapies T-cell receptor NFAT T-Cell Listeria monocytogenes Recombinant Proteins Cell biology Transcription Factor AP-1 medicine.anatomical_structure Infectious Diseases Gene Expression Regulation Cancer research Development of treatments and therapeutic interventions CD8 Biotechnology |
| Zdroj: | Immunity, vol 42, iss 2 Immunity 42, 265–278 (2015) |
| ISSN: | 1074-7613 |
| DOI: | 10.1016/j.immuni.2015.01.006 |
| Popis: | During persistent antigen stimulation, CD8(+) Tcells 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 Tcell exhaustion. When expressed in cells, an engineered form of NFAT1 unable to interact with AP-1 transcription factors diminished Tcell receptor (TCR) signaling, increased the expression of inhibitory cell surface receptors, and interfered with the ability of CD8(+) Tcells to protect against Listeria infection and attenuate tumor growth invivo. We defined the genomic regions occupied by endogenous and engineered NFAT1 in primary CD8(+) Tcells and showed that genes directly induced by the engineered NFAT1 overlapped with genes expressed in exhausted CD8(+) Tcells invivo. Our data show that NFAT promotes Tcell anergy and exhaustion by binding at sites that do not require cooperation with AP-1. |
| Databáze: | OpenAIRE |
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