Adrenal stress response is an essential host response against lethal T cell activation

Cytokine release syndrome (CRS) is a major cause of death in lethal T cell activation and presents a significant barrier for CAR-T immunotherapy or allogenic hematopoietic cell transplantation. We reported here that adrenal stress response, defined by a 5-10-fold increase in induced glucocorticoid (iGC) production, is an essential host response against lethal T cell activation. We identified scavenger receptor BI (SR-BI), a HDL receptor, as a key regulator for iGC production. Using SR-BI null mice as an adrenal stress response deficiency model, we demonstrated that adrenal stress response protects anti-CD3 induced death through keeping CRS under control and relative adrenal insufficiency (RAI) – lacking adrenal stress response, is a risk factor. To understand how induced glucocorticoid (iGC) regulates CRS in lethal T cell activation, we conducted single cell RNA sequencing analysis of splenocytes from SR-BI+/+ and SR-BI-/- mice at 20h post anti-CD3 challenge.