OL responses are directly and indirectly influenced by cell-cell interactions with immune cells and other glia. For instance, differentiation of OL lineage cells generated from MS patient iPSCs occurs efficiently in vitro and in vivo168, yet is inhibited by exposure to peripheral blood mononuclear cell supernatants, with CD4+ T cell-derived interferon (IFN)-γ being a prime contributor169. IFNγ can also induce OPC death indirectly, via enhanced CD8+ T cell infiltration and subsequent antigen presentation by OPCs99. Primary human adult OLs undergo cell death in vitro following exposure to several T cell populations and natural killer cells, occurring in part through NKG2C/D receptor-ligand interactions37,38; OLs express the ligands in MS lesions thereby making them susceptible to immune mediated cytotoxicity37,38. Furthermore, direct contact of OLs with T helper (Th) 17 cells promotes glutamate release that alters OL cholesterol biosynthesis, thereby causing stress, reducing process formation, and increasing death39. In EAE, ultrastructural analysis demonstrated infiltrating monocytes appearing to pull myelin off the axon170; together with the known requirement of monocytes to initiate disease in EAE171, this suggests an important interaction between monocytes and myelin
