MHC II expression by donor bone marrow-derived macrophages underpins neuroinflammation and cognitive deficits during murine chronic GVHD

Abstract

Abstract Chronic graft-versus-host disease (cGVHD) remains the leading cause of non-relapse mortality after allogeneic stem cell transplantation (SCT) for haematological malignancies. Manifestations of GVHD in the central nervous system (CNS) present as neurocognitive dysfunction in a significant proportion of patients. Neuroinflammation in the cortex of mice and humans in acute GVHD is dependent on host resident microglia-derived TNF. However, the mechanisms driving cGVHD in the CNS are yet to be elucidated. Here, our studies of murine cGVHD revealed a hippocampal-dependent spatial learning and memory deficit associated with inflammation and persistent IFN-γ upregulation. Hippocampal RNA sequencing identified perturbations to structural and functional synapse-related gene expression, in the context of upregulated genes associated with antigen presentation and IFN-γ responses. Brain T cell infiltration was initially dominated by CD8 T cells with an eventual expansion in CD4 T cells, in parallel with a marked infiltration of MHC Class II-expressing bone marrow-derived macrophages (BMDM). After day 70, BMDM constituted 50% of the brain macrophage pool and exhibited a transcriptional signature distinct from host resident microglia. Transfer of MHC class II–deficient BM grafts resulted in attenuated neuroinflammation, implicating donor BMDM as critical mediators of CNS cGVHD. Our identification of the hippocampus as a cGVHD target, and disease mediators distinct from those in the acute phase, highlights the necessity to pursue alternative therapeutic targets for late-stage neurological manifestations post-SCT.