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

By G. Martinez, R. M. Pereira, Tarmo Äijö, Edward Y. Kim, F. Marangoni, M. Pipkin, Susan M. Togher, V. Heissmeyer, Yi C. Zhang, Shane Crotty and 6 more. Immunity, 2015

734 citations recorded by the source corpus.

SUMMARY 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.

Subfields: Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/9041c41c2316b1235a88b88a198efe95a8ec58cc

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Citations in the corpus

Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq (2016, positive): “Another variable gene of interest was the transcription factor NFATC1; previously implicated in T cell exhaustion (49).”
TOX and TOX2 transcription factors cooperate with NR4A transcription factors to impose CD8+ T cell exhaustion (2019, background): “We also examined cells expressing CA-RIT-NFAT1, a constitutively active version of NFAT1 that cannot interact with AP-1 (19, 20); CA-RIT-NFAT1 induces a transcriptional program very similar to exhaustion both in vitro and in vivo (20, 21), whereas another mutated version of CA-RIT-NFAT1 that cannot ”
Overcoming T cell exhaustion in infection and cancer (2015, background): “Moreover, NFAT binding in the absence of AP-1 appears to promote expression of some features of an exhausted transcriptional program [128].”
CDK4/6 Inhibition Augments Anti-Tumor Immunity by Enhancing T Cell Activation (2017, background): “The digested NFATc3 and His-GB1 were separated and further purified using size exclusion chromatography (GE Healthcare Life Sciences “Superdex 75 10/300 GL”).”