β2-Microglobulin Regulates Extracellular Matrix Dynamics During Peripheral Nerve Injury

Peripheral nerve injury initiates a complex cascade of events coordinating immune responses, extracellular matrix (ECM) remodeling, and neuronal repair. While β2-microglobulin (B2M) is well known for its role in MHC class I-mediated antigen presentation and CD8⁺ T-cell differentiation, its potential contributions to non-immune processes remain underexplored. In this study, we investigated the role of B2M in peripheral nerve regeneration using a chronic constriction injury (CCI) model in wild-type and B2M-deficient (B2M-KO) mice. Flow cytometry, RNA sequencing (RNA-seq), and quantitative PCR (qPCR) were performed to assess T-cell subset dynamics and gene expression following injury. Flow cytometric analysis showed that CD3⁺CD4⁺ and CD3⁺CD8⁺ T-cell populations increased by day 7 post-injury. While CD3⁺CD4⁺ T-cell expansion occurred in both groups, a significant increase in CD3⁺CD8⁺ T cells was observed only in wild-type mice. RNA-seq analysis at 3 days post-injury-prior to substantial T-cell accumulation-revealed marked downregulation of ECM-related genes in B2M-KO mice, including collagens, matrix-associated proteins, and other key ECM components. KEGG analysis identified suppression of ECM-receptor interaction, PI3K-Akt, and TGF-β signaling pathways. qPCR confirmed reduced expression of Thbs1 in B2M-KO mice. These findings suggest that B2M plays a critical, CD8⁺ T-cell-independent role in regulating ECM dynamics and regenerative signaling during early nerve repair, expanding the conceptual framework of B2M's function beyond classical immune roles.