The autophagy-inhibitory tissue hormone DBI/ACBP is essential for glucocorticoid-induced immunosuppression

: Systemic administration of glucocorticoids (GCs) has immunosuppressive effects that involve the upregulation of the transcription factor TSC22D3 in dendritic cells (DCs), thereby reducing their capacity for antigen presentation to T lymphocytes. Recently, we found that this effect is not mediated by direct action on the GC receptor in DCs but rather involves an indirect signaling circuitry. Indeed, GCs act on the GC receptor expressed by many cell types to cause the upregulation and release of the tissue hormone DBI/ACBP (diazepam binding inhibitor, acyl-CoA binding protein). DBI/ACBP, which is an inhibitor of macroautophagy/autophagy, then acts on the benzodiazepine-binding site of the gamma-aminobutyric acid type A receptor (GABAAR) to elicit the upregulation of TSC22D3. The indirect, DBI/ACBP-dependent upregulation of TSC22D3 by GCs is observed both in vivo (mice) and in vitro, in murine splenocytes and bone marrow-derived DCs, as well as in human peripheral blood mononuclear cells and monocyte-derived DCs. Inhibition of human mixed lymphocyte reactions (confronting DCs and lymphocytes from distinct donors) by DCs is reduced by DBI/ACBP neutralizing antibodies. Similarly, the suppression of antitumor immune responses (elicited by vaccination with dying cancer cells, immunogenic chemotherapy or PDCD1/PD-1 blockade) by GCs is reversed by DBI/ACBP neutralization. Epistatic experiments indicate that knockout of Tsc22d3 in DCs and inhibition of DBI/ACBP act on the pathway to reverse GC-mediated inhibition of cancer immunosurveillance. Of note, the benzodiazepine diazepam restores GC-induced immunosuppression when DBI/ACBP is inhibited. Altogether, these findings support a role for the DBI/ACBP-GABAAR system in immunosuppression by GCs.