REGULATORY NEUTROPHILS IN MULTIPLE SCLEROSIS AND THEIR ROLE IN IMMUNOSURVEILLANCE

Aim: Neutrophils appear to play a role in the progression of autoimmune diseases due to their function as effector of the innate immune system. Programmed cell death receptor 1 (PD-1) and its ligands, PD-L1 and PD-L2, are key inhibitors in immune response. Despite their well-established pro-inflammatory role, we identified a subpopulation of immunosuppressive neutrophils expressing PD-L2 in both multiple sclerosis (MS) patients and experimental autoimmune encephalomyelitis (EAE) mice. These finding provides new insights in the involvement of PD-L2+ cells in neuroinflammation.
Methods: Using EAE as a model of MS, we employed transgenic mouse to selectively deplete PD-L2+ myeloid population. Human resting neutrophils were collected, isolated using Ficoll-Paque density gradient separation, cultured with various stimuli, and analysed via flow cytometry. For mouse dural meninges, the tissue was peeled from the skullcap and stained for immunofluorescence.
Results: We identified a new population of immunosuppressive PD-L2+ neutrophils that is increased in MS patients. In human, following RNA-seq analysis, flow cytometry confirmed that PD-L2 expression can be induced using varying concentrations of type I interferons. In mice’s dura, under inflammatory conditions, PD-L2+ cells circulate within the dural meningeal lymphatic vessels (MLVs). After a skullcap transplantation with a reporter mouse, the skull bone marrow niches appeared to be a new possible peculiar source of them.
Conclusion: Our preliminary results support the protective existence of these distinct PD-L2+ cells in neuroinflammation. They may also participate in immune surveillance within the dural MLVs, potentially contributing to the initiation of immune responses.

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