During chronic GVHD, donor CD8⁺ T cells infiltrate the brain, followed by CD4⁺ T cells and donor bone marrow–derived macrophages (BMDMs). The level of IFN-γ, which is predominantly secreted by activated lymphocytes, is increased in the brain, resulting in higher expression of MHC class II on donor-derived macrophages. These immune attacks against synapses in the brain lead to chronic GVHD of the CNS. See the visual abstract for the article by Adams et al.¹