Protection of Antigen-Primed Effector T Cells From Glucocorticoid-Induced Apoptosis in Cell Culture and in a Mouse Model of Multiple Sclerosis

Induction of T cell apoptosis constitutes a major mechanism by which therapeutically administered glucocorticoids (GCs) suppress inflammation and associated clinical symptoms, for instance in multiple sclerosis (MS) patients suffering from an acute relapse. The sensitivity of T cells to GC action depends on their maturation and activation status, but the precise effect of antigen-priming in a pathological setting has not been explored. Here we used transgenic and congenic mouse models to compare GC-induced apoptosis between naive and antigen-specific effector T cells from mice immunized with a myelin peptide. Antigen-primed effector T cells were protected from the pro-apoptotic activity of the synthetic GC dexamethasone in a dose-dependent manner, which resulted in their accumulation relative to naive T cells in vitro and in vivo. Notably, the differential sensitivity of T cells to GC-induced apoptosis correlated with their expression level of the anti-apoptotic proteins Bcl-2 and Bcl-X-L and a loss of the mitochondrial membrane potential. Moreover, accumulation of antigen-primed effector T cells following GC treatment in vitro resulted in an aggravated disease course in an adoptive transfer mouse model of MS in vivo, highlighting the clinical relevance of the observed phenomenon. Collectively, our data indicate that antigen-priming influences the T cells' sensitivity to therapeutically applied GCs in the context of inflammatory diseases.

Automated summary

The study investigated the impact of antigen priming on the sensitivity of T cells to glucocorticoid-induced apoptosis, revealing the different responses of antigen-primed effector T cells compared to naïve T cells to synthetic GCs in vitro and in vivo. The findings suggest that antigen priming influences the sensitivity of T cells to therapeutic GCs in the context of inflammatory diseases.