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Exhaustion

Cancer- and infection-induced T cell exhaustion are distinct

Nature Immunology volume 24, pages 1604–1605 (2023)Cite this article

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The transcription factor NFAT5 regulates T cell exhaustion, a dysfunctional state caused by chronic exposure to antigen and other signals, during cancer but not during chronic viral infection.

CD8+ T cell exhaustion is a dysfunctional differentiation state that is caused by chronic exposure to antigen and signals from the microenvironment1. CD8+ T cell exhaustion, driven by chronic antigen exposure, can occur in both cancer and chronic infection and is correlated with negative outcomes in patients with cancer1,2. Chronic infection is frequently used as a model to study T cell exhaustion, and despite differences in microenvironmental conditions, lessons learned from infection are often applied to cancer settings. Yet how exhaustion-promoting signals differ between tumors and infection is not well understood. In this issue of Nature Immunology, Tillé et al.3 show that the transcription factor NFAT5, which is upregulated in CD8+ T cells in human and mouse tumors and in mouse models of chronic infection, becomes active only in the hyperosmotic tumor microenvironment, where it exacerbates an exhaustion signature induced by NFAT1 and NFAT2. These data support a model whereby NFAT5 acts as an environmental sensor that reinforces an exhaustion transcriptional program specifically in the tumor microenvironment.

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Fig. 1: NFAT5 acts as an osmotic sensor in the tumor microenvironment.

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Authors and Affiliations

  1. Yale University School of Medicine, Department of Immunobiology, New Haven, CT, USA

    Jessica Buck & Nikhil S. Joshi

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  1. Jessica Buck
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  2. Nikhil S. Joshi
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Correspondence to Nikhil S. Joshi.

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N.S.J. has consulted for Dragonfly Therapeutics, in areas unrelated to this topic.

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Buck, J., Joshi, N.S. Cancer- and infection-induced T cell exhaustion are distinct. Nat Immunol 24, 1604–1605 (2023). https://doi.org/10.1038/s41590-023-01624-9

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