Stroke severity is worsened by recruitment of inflammatory immune cells into the brain. This process depends in part on T cell activation, in which the B7 family of co-stimulatory molecules plays a pivotal role. Previous studies demonstrated more severe infarcts in mice lacking Programmed Death-1 (PD-1), a member of the B7 family, thus implicating PD-1 as a key factor in limiting stroke severity. The purpose of this study was to determine if this protective effect of PD-1 involves either of its ligands, PD-L1 and PD-L2. Thus, CNS inflammation and stroke severity were evaluated in male PD-L1 and PD-L2 knockout (KO) mice undergoing 60 min middle cerebral artery occlusion (MCAO) followed by 96 h reperfusion. Unexpectedly, PD-L1 KO and to a lesser extent PD-L2 KO mice had reduced levels of activated microglia and infiltrating monocytes and total infarct volume compared to wild-type mice, as well as reduced splenic atrophy and MHC class II expression, suggesting a pathogenic rather than a regulatory role for both PD-ligands. Both positive and negative regulatory roles have been suggested for the PD-ligands in context of various diseases and our novel observations indicate that PD-L1 and PD-L2 might have proinflammatory functions independent of PD-1 binding that worsen stroke outcome. These results suggest the possibility of using antibodies to PD-L1/2 as a potential treatment for human stroke patients.
- Copyright © 2013 by The American Association of Immunologists, Inc.