Evaluating the Role of MeCP2 on Regulating the Antiviral CD8+ T cell Response
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Date
2025-05
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The Ohio State University
Abstract
Methyl-CpG binding protein 2 (MeCP2) regulates gene transcription by reading DNA methylation patterns. Mutations in MECP2 cause Rett syndrome (RTT), a neurodevelopmental disease that renders patients susceptible to severe respiratory infection, but how the loss of MeCP2 affects the immune response to respiratory infection remains unknown. Using a murine model of RTT, we asked how the loss of MeCP2 (Mecp2-/y) impacts the host response to Influenza A virus (A/Puerto Rico/8/34; IAV). Infected Mecp2-/y mice were more susceptible to virus-induced lung disease and had a higher mortality rate than wild-type infected mice. Lung transcriptional profiling following infection revealed that Mecp2-/y mice showed significantly delayed induction of genes associated with CD8+ T cell responses. In line with our transcriptional findings, we observed significantly lower lung recruitment of IAV-specific CD8+ T cells, identified by flow cytometry, in Mecp2-/y mice compared to WT mice. As CD8+ T cells are essential for clearing infectious viruses, we measured viral burden in the lungs and observed delayed viral clearance in Mecp2-/y mice. These findings suggest a role of MeCP2 in regulating CD8+ T cells, particularly during IAV infection. To closely examine if MeCP2 impacts cell intrinsic mechanisms regulating CD8+ T cells, we examined the gene expression profiles of isolated naïve CD8+ T cells from the spleens of WT and Mecp2-/y mice. Gene set enrichment analysis revealed positive enrichment of cell death pathways and negative enrichment of T cell receptor signaling components, indicating that MeCP2 regulates CD8+ T cell survival and activation. Future work will leverage an in vitro CD8+ T cell activation model, in which levels of stimuli can be experimentally manipulated, to identify mechanisms by which MeCP2 regulates CD8+ T cell survival, activation, and proliferation. Overall, this project aims to distinguish between potential cell-intrinsic and cell-extrinsic processes regulated by MeCP2 that shape essential antiviral CD8+ T cell response. These findings could hold significant clinical implications by helping illuminate the mechanisms that lead to severe respiratory infection amongst RTT patients.
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Keywords
MeCP2, antiviral response, Rett Syndrome, Influenza A