RRC ID 58233
Author Maeda N, Maruhashi T, Sugiura D, Shimizu K, Okazaki IM, Okazaki T.
Title Glucocorticoids potentiate the inhibitory capacity of programmed cell death 1 by up-regulating its expression on T cells.
Journal J Biol Chem
Abstract The inhibitory co-receptor programmed cell death 1 (PD-1, Pdcd1) plays critical roles in the regulation of autoimmunity, anticancer 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 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. GC-induced up-regulation of PD-1 depended on transactivation of PD-1 transcription mediated through the glucocorticoid receptor. We further found that a GC response element 2525 bp upstream of 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, 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.
Volume 294(52)
Pages 19896-19906
Published 2019-12-27
DOI 10.1074/jbc.RA119.010379
PII RA119.010379
PMID 31723031
PMC PMC6937557
MeSH Animals Anti-Inflammatory Agents / pharmacology CD8-Positive T-Lymphocytes / cytology CD8-Positive T-Lymphocytes / immunology CD8-Positive T-Lymphocytes / metabolism Cells, Cultured Dexamethasone / pharmacology Glucocorticoids / pharmacology* Mice Mice, Inbred BALB C Mice, Inbred C57BL Programmed Cell Death 1 Receptor / genetics Programmed Cell Death 1 Receptor / metabolism* Promoter Regions, Genetic Receptors, Glucocorticoid / metabolism T-Lymphocytes / cytology T-Lymphocytes / immunology T-Lymphocytes / metabolism Transcription Initiation Site Transcriptional Activation / drug effects Up-Regulation / drug effects*
IF 4.238
Times Cited 2
Resource
DNA material B6N Mouse BAC clone (RDB07573) B6Ng01- 240G08