The PD-1/PD-L1 (programmed cell death protein 1/programmed cell death ligand 1) axis plays an important role in the adaptive immune system and has influence on neoplastic and inflammatory diseases. The role of the PD-1/PD-L1 axis in multiple sclerosis (MS) has not yet been investigated in detail. We aimed to delineate distinct expression patterns in peripheral blood mononuclear cell (PBMC) subsets and to evaluate the role of soluble PD-1/PD-L1 in the context of MS. 

PD-L1/PD-1 also exist in soluble forms (sPD-L1/sPD-1)  shedded from cellular surfaces. In systemic autoimmune diseases, sPD-1/sPD-L1 serum levels and membrane-bound PD-1/PD-L1 on T and antigen-presenting cells are linked to disease activity and treatment response. In MS, the PD-1/PD-L1 axis and in particular the role of soluble PD-1/PD-L1 is poorly understood but may offer relevance as disease marker and potential target for therapeutic intervention.

In depth immunophenotyping by flow cytometry was performed on PBMCs of 49 patients with relapsing-remitting MS (RRMS) and 27 controls. sPD-1/sPD-L1 serum levels were analyzed in a cohort of 84 patients with RRMS and 36 controls. To evaluate the therapeutic potential of soluble PD-L1, 600 µg/kg recombinant protein was systemically administered in Experimental Autoimmune Encephalomyelitis (EAE), an animal model of MS. 

Patients with RRMS displayed distinct cellular PD-1/PD-L1 expression patterns in PBMCs and an association of sPD-L1 with MS subtype and disease severity. Systemic administration of recombinant PD-L1 in EAE resulted in ameliorated disease severity and reduced infiltration of peripheral immune cells into the CNS. 

The marked expression of PD-1/PD-L1 in immune cell subsets of patients with RRMS, and the correlation of sPD-L1 with disease-severity offers promising potential for the use as a serum marker in the context of MS. Furthermore, enhancement of coregulatory PD-1/PD-L1 signaling by exogenous supplementation of sPD-L1 may serve as a novel therapeutic strategy for severe stages of acute neuroinflammation.