Glucocorticoids potentiate the inhibitory capacity of programmed cell death 1 by up-regulating its expression on T cells

The inhibitory co-receptor programmed cell death 1 (PD-1, Pdcd1) plays critical roles in the regulation of autoimmunity, anti-cancer immunity, and immunity against infections. Immunotherapies targeting PD-1 have revolutionized cancer management and instigated various trials of improved cancer immunotherapies. Moreover, extensive trials are underway to potentiate PD-1 function in order to suppress harmful immune responses. Here, we found that both natural and synthetic glucocorticoids (GCs) up-regulate PD-1 on T cells without altering the expression levels of other co-receptors and cell-surface molecules. The GC-induced up-regulation of PD-1 depended on the transactivation of PD-1 transcription mediated through the glucocorticoid receptor (GR). We further found that a GC response element (GRE) 2525 bp upstream from the transcription start site of Pdcd1 is responsible for GC-mediated transactivation. We also observed that in vivo administration of GCs significantly up-regulates PD-1 expression on tumor-infiltrating T cells. By analyzing T cells differing in PD-1 expression, we directly demonstrated that the amount of PD-1 on the cell surface correlates with its inhibitory effect. Accordingly, GCs potentiated the capacity of PD-1 to inhibit T cell activation, suggesting that this PD-1-mediated inhibition contributes, at least in part, to the anti-inflammatory and immunosuppressive effects of GCs. In light of the critical roles of PD-1 in the regulation of autoimmunity regulation, we expect that the potentiation of PD-1 activity may offer a promising therapeutic strategy for managing inflammatory and autoimmune diseases. Our current findings provide a rationale for strategies seeking to enhance the inhibitory effect of PD-1 by increasing its expression level.

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本論文は，著者Natsumi Maedaの学位論文として提出され，学位審査・授与の対象となっている。
This research was originally published in the Journal of Biological Chemistry. Natsumi Maeda, Takumi Maruhashi, Daisuke Sugiura, Kenji Shimizu, Il-mi Okazaki, and Taku Okazaki. Glucocorticoids potentiate the inhibitory capacity of programmed cell death 1 by up-regulating its expression on T cells. J Biol Chem. 2019; 294(52):19896-19906.

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