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Glucocorticoids in T cell development, differentiation and function

Abstract

Glucocorticoids (GCs) are small lipid hormones produced by the adrenals that maintain organismal homeostasis. Circadian and stress-induced changes in systemic GC levels regulate metabolism, cardiovascular and neural function, reproduction and immune activity. Our understanding of GC effects on immunity comes largely from administration of exogenous GCs to treat immune or inflammatory disorders. However, it is increasingly clear that endogenous GCs both promote and suppress T cell immunity. Examples include selecting an appropriate repertoire of T cell receptor (TCR) self-affinities in the thymus, regulating T cell trafficking between anatomical compartments, suppressing type 1 T helper (TH1) cell responses while permitting TH2 cell and, especially, IL-17-producing T helper cell responses, and promoting memory T cell differentiation and maintenance. Furthermore, in addition to functioning at a distance, extra-adrenal (local) production allows GCs to act as paracrine signals, specifically targeting activated T cells in various contexts in the thymus, mucosa and tumours. These pleiotropic effects on different T cell populations during development and immune responses provide a nuanced understanding of how GCs shape immunity.

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Fig. 1: Glucocorticoid synthetic pathway.
Fig. 2: Glucocorticoids antagonize negative selection.
Fig. 3: Paracrine glucocorticoid signalling in the thymus.
Fig. 4: GC regulation of effector CD4+ T cell differentiation.
Fig. 5: Circulating glucocorticoids regulate T cell trafficking and resulting effector and memory responses.

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Acknowledgements

The authors thank J. A. Cidlowski, R. Bosselut and N. H. Prior for critical reading of the manuscript. This work was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH).

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Taves, M.D., Ashwell, J.D. Glucocorticoids in T cell development, differentiation and function. Nat Rev Immunol 21, 233–243 (2021). https://doi.org/10.1038/s41577-020-00464-0

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