Our laboratory discovered that CD4-positive (CD4⁺) T cells of the immune system convey transitory neuroprotection to injured mouse facial motoneurons (FMNs) (Serpe et al., , , ). A fundamental question in the mechanisms responsible for neuroprotection concerns the identity of the cell(s) that serves as the antigen-presenting cell (APC) to activate the CD4⁺ T cells. Here, we first establish that CD4⁺ T cells reactive to non-CNS antigen fail to support FMN survival and, second, demonstrate a two-compartment model of CD4⁺ T cell activation. Mouse bone marrow (BM) chimeras were developed that discriminate between resident antigen-presenting host cell and BM-derived antigen-presenting donor cell expression of major histocompatibility complex II within central and peripheral compartments, respectively. After facial nerve transection, neither compartment alone is sufficient to result in activated CD4⁺ T cell-mediated FMN survival. Rather, CD4⁺ T cell-mediated neuroprotection appears to depend on both resident microglial cells in the central compartment and a BM-derived APC in the peripheral compartment. This is the first in vivo report demonstrating a neuroprotective mechanism requiring APC functions by resident (i.e., parenchymal) microglial cells.