MHC class I H2-Kb negatively regulates neural progenitor cell proliferation by inhibiting FGFR signaling

Abstract

Proteins of the major histocompatibility complex class I (MHC I), predominantly known for antigen presentation in the immune system, have recently been shown to be necessary for developmental neural refinement and adult synaptic plasticity. However, their roles in nonneuronal cell populations in the brain remain largely unexplored. Here, we identify classical MHC I molecule H2-Kb as a negative regulator of proliferation in neural stem and progenitor cells (NSPCs). Using genetic knockout mouse models and in vivo viral-mediated RNA interference (RNAi) and overexpression, we delineate a role for H2-Kb in negatively regulating NSPC proliferation and adult hippocampal neurogenesis. Transcriptomic analysis of H2-Kb knockout NSPCs, in combination with in vitro RNAi, overexpression, and pharmacological approaches, further revealed that H2-Kb inhibits cell proliferation by dampening signaling pathways downstream of fibroblast growth factor receptor 1 (Fgfr1). These findings identify H2-Kb as a critical regulator of cell proliferation through the modulation of growth factor signaling.

Blood-to-brain communication in aging and rejuvenation

“…Interestingly, B2M and MHC-I genes are upregulated in various cell types in the aged brain 32,43,67 , and direct delivery of B2M into the hippocampus also impairs neurogenesis and cognition. These detrimental effects were abrogated in mice that lack surface expression of classical MHC-I, indicating that its molecular effect may depend on the specific repertoire of MHC-I molecules expressed on individual cell types in the brain [67][68][69] . Aged mice lacking B2M display increased neurogenesis and enhanced cognition, suggesting that targeting B2M may be a viable therapeutic avenue to restore function to the aged brain 48 .…”

Loss of neuronal Tet2 enhances hippocampal-dependent cognitive function

“…All plasmids were validated by Sanger sequencing prior to virus production. LV particles were generated as previously described ( Lin et al, 2021 ) with viral titers between 1.2 × 10 9 to 1.5 × 10 9 viral particles per mL. Knockdown and overexpression of Tet2 was validated by qRT-PCR.…”

“…Sterotaxic injections were performed according to the protocol previously described ( Lin et al, 2021 ). Animals were placed in a stereotaxic frame and anesthetized with 2% isoflurane (Patterson Veterinary) (2 L per min oxygen flow rate) delivered through an anesthesia nose cone.…”

Single-cell transcriptomics highlights immunological dysregulations of monocytes in the pathobiology of COPD

“…5C and Additional file 2: Fig. S5G-S5I), and the up-regulation of these IFN receptors together with their ligands was also observed in the aged nervous system [34][35][36], which reportedly resulted in an increased level of MHC class I molecules in aged neurons [34]. Correspondingly, vital components of the MHC I system, especially β2-microglobulin (B2M), showed a general up-regulation in aged airway epithelial cells (Fig.…”

“…5 C). Given that club cells are multifunctional bronchoalveolar epithelial progenitor cells that are of great importance to airway epithelium maintenance [ 39 ], such negative correlations raised the possibility that the autoimmunity of aged club cells may compromise their stemness through the modulation of FGF signaling, as was reported in other types of progenitor cells and stem cells [ 35 ]. Concordantly, we further identified an autoimmune-prone sub-cluster unique to aged club cells (Fig.…”