Oligodendrocyte precursor cells present antigen and are cytotoxic targets in inflammatory demyelination

Abstract

Oligodendrocyte precursor cells (OPCs) are abundant in the adult central nervous system, and have the capacity to regenerate oligodendrocytes and myelin. However, in inflammatory diseases such as multiple sclerosis (MS) remyelination is often incomplete. To investigate how neuroinflammation influences OPCs, we perform in vivo fate-tracing in an inflammatory demyelinating mouse model. Here we report that OPC differentiation is inhibited by both effector T cells and IFNγ overexpression by astrocytes. IFNγ also reduces the absolute number of OPCs and alters remaining OPCs by inducing the immunoproteasome and MHC class I. In vitro, OPCs exposed to IFNγ cross-present antigen to cytotoxic CD8 T cells, resulting in OPC death. In human demyelinated MS brain lesions, but not normal appearing white matter, oligodendroglia exhibit enhanced expression of the immunoproteasome subunit PSMB8. Therefore, OPCs may be co-opted by the immune system in MS to perpetuate the autoimmune response, suggesting that inhibiting immune activation of OPCs may facilitate remyelination.

Remyelination alters the pattern of myelin in the cerebral cortex

“…Although OPCs are slightly less abundant in the deeper layers compared to the surface 100 μm (Supplementary Figure 3A,C,D) ( p = 2.084 × 10 −13 , N-way ANOVA, by depth), there was no evidence of persistent OPC depletion during recovery (Supplementary Figure 3D,F) ( p = 0.086, Kruskal-Wallis one-way ANOVA). Reactive astrocytes, a known pathological feature of both the cuprizone model and cortical demyelinating lesions (Chang et al, 2012; Skripuletz et al, 2008), can impair OPC differentiation by secreting cytokines (Kirby et al, 2019; Su et al, 2011; Zhang et al, 2010), but whether reactive astrocytes impair recovery differently as a function of cortical depth is unknown. GFAP+ astrocytes are relatively rare in the deeper (200-500 μm) regions of cortex in naïve mice; however, following cuprizone-treatment, their number increased nearly ten-fold ( p = 5.86 × 10 −16 , N-way ANOVA, by time-point).…”

“…The inability to recover fully from a demyelinating event raises the possibility that inflammation persists long after the initial trauma, or that OPCs in these regions are permanently altered as a result of exposure to this environment, if only for a short time (Baxi et al, 2015; Kirby et al, 2019). Like other progenitor cells, OPCs exhibit a decline in regenerative potential with age and can undergo senescence, a process that may be accelerated by exposure to inflammatory cytokines (Kirby et al, 2019; Neumann et al, 2019; Nicaise et al, 2019). It is also possible that there is a restricted time period during which OPCs can detect and respond to myelin loss; if there are inherent limits on OPC mobilization, as suggested by the uniform behavior of OPCs across cortical layers, then the inability to match the demand for new cells early may lead to prolonged deficits.…”

T cell infiltration in both human multiple system atrophy and a novel mouse model of the disease

“…Briefly, striatums were triturated and digested with 1 mg/mL Collagenase IV (Sigma) and 20 μg/mL DNAse I (Sigma) diluted in RPMI 1640 with 10% heat inactivated fetal bovine serum, 1% l-glutamine (Sigma), and 1% Penicillin-Streptomycin (Sigma). Mononuclear cells were separated out using a 30/70% percoll gradient (GE) as previously described [30]. For deep cervical lymph nodes, lymph nodes were isolated and subsequently disassociated through a 70 μm filter.…”

Oligomeric amyloid beta prevents myelination in a clusterin-dependent manner

“…In pathological conditions, OPCs can upregulate cytokine production in response to IL-17 signaling and greatly contribute to CNS pathogenesis 17 . Surprisingly, OPCs also upregulate antigen presentation machinery in the demyelinating CNS, and can regulate T cell function [18][19][20] . Taken together, these studies illustrate the dynamic role OPCs can play in the adult CNS and build a strong case in support of exploring adult OPCs diversity at the transcriptional level.…”