PD-1 Interaction with PD-L1 but not PD-L2 on B-cells Mediates Protective Effects of Estrogen against EAE

Increased remissions in multiple sclerosis (MS) during late pregnancy may result from high levels of sex steroids such as estrogen and estriol. Estrogen (E2=17β-estradiol) protects against experimental autoimmune encephalomyelitis (EAE), but the cellular basis for E2-induced protection remains unclear. Treatment with relatively low doses of E2 can protect against clinical and histological signs of MOG-_35-55 induced EAE through mechanisms involving the PD-1 coinhibitory pathway and B-cells. The current study evaluated the contribution of PD-1 ligands, PD-L1 and PD-L2, on B-cells in E2-mediated protection against EAE in WT, PD-L1^-/- and PD-L2^-/- mice. Unlike PD-L2^-/- mice that were fully protected against EAE after E2 treatment, E2-implanted PD-L1^-/- mice were fully susceptible to EAE, with increased numbers of proliferating Th1/Th17 cells in the periphery and severe cellular infiltration and demyelination in the CNS. Moreover, transfer of B-cells from MOG-immunized PD-L1^-/- or PD-L2^-/- donors into E2-preconditioned B-cell deficient μMT^-/- recipient mice revealed significantly reduced E2-mediated protection against EAE in recipients of PD-L1^-/- B-cells, but near-complete protection in recipients of PD-L2^-/- B-cells. We conclude that PD-1 interaction with PD-L1 but not PD-L2 on B-cells is crucial for E2-mediated protection in EAE and that strategies that enhance PD-1/PD-L1 interactions might potentiate E2 treatment effects in MS.