Chemokine-mediated redirection of T cells is critically involved in glucocorticoid therapy of multiple sclerosis

Glucocorticoids (GCs) are the standard therapy for acute disease bouts in multiple sclerosis (MS) patients but their exact mechanisms remain unclear. We have used experimental autoimmune encephalomyelitis (EAE) as a model of MS in combination with different transgenic mice to obtain new insight into the mode of action used by GCs to ameliorate neuroinflammation. We have previously reported that T cells are the main targets of GCs in the treatment of EAE. Surprisingly, it now turned out that induction of T cell apoptosis was fully dispensable for the beneficial effects of GCs as they efficiently ameliorated EAE in mouse mutants that are refractory to GC-induced apoptosis. Analyses performed in mice as well as human patients rather identified GC effects on T cell migration in response to chemokines as a critical mechanistic principle in MS therapy. GCs enhanced the responsiveness to CXCL12 and inhibition of the corresponding chemokine receptor CXCR4 strongly impaired the capacity of GCs to interfere with EAE as revealed by an aggravated disease course and more pronounced CNS infiltration. Importantly, a similar GC effect on T cells was also identified in a variety of MS patients undergoing methylprednisolone pulse therapy. Our findings therefore suggest that the treatment of neuroinflammatory diseases by GCs depends on the redirection of T cells rather than apoptosis induction.