Role of lamin A/C on dendritic cell function in antiviral immunity

• DOI: 10.1007/s00018-024-05423-9
• Publication Date: 2024-09-12T05:02:20Z
• Authors: Beatriz Herrero-F...; Marina Ortega-Zapero; Raquel Gómez-Bris; Angela Sáez; Salvador Iborra; Virginia Zorita; Ana Quintas; Enrique Vázquez; Ana Dopazo; Francisco Sánchez...; Silvia Magdalena ...; Jose Maria Gonzál...
• Keywords: 612.017; 2412 Inmunología; Immunological Synapses; Medicina; Biología; 2407 Biología Celular; 2415 Biología Molecular; Vaccinia virus; CD8-Positive T-Lymphocytes; Mice; Vaccinia; Animals; Mice, Knockout; Lamin A/C; Gene accessibility regulation; NF-kappa B; Granulocyte-Macrophage Colony-Stimulating Factor; Dendritic Cells; Th1 Cells; Lamin Type A; Mice, Inbred C57BL; Original Article; Dendritic cell; Viral immune response; NFκB; T-Lymphocytes, Cytotoxic

AbstractDendritic cells (DCs) play a crucial role in orchestrating immune responses, particularly in promoting IFNγ-producing-CD8 cytotoxic T lymphocytes (CTLs) and IFNγ-producing -CD4 T helper 1 (Th1) cells, which are essential for defending against viral infections. Additionally, the nuclear envelope protein lamin A/C has been implicated in T cell immunity. Nevertheless, the intricate interplay between innate and adaptive immunity in response to viral infections, particularly the role of lamin A/C in DC functions within this context, remains poorly understood. In this study, we demonstrate that mice lacking lamin A/C in myeloid LysM promoter-expressing cells exhibit a reduced capacity to induce Th1 and CD8 CTL responses, leading to impaired clearance of acute primaryVaccinia virus(VACV) infection. Remarkably,in vitro-generated granulocyte macrophage colony-stimulating factor bone marrow-derived DCs (GM-CSF BMDCs) show high levels of lamin A/C. Lamin A/C absence on GM-CSF BMDCs does not affect the expression of costimulatory molecules on the cell membrane but it reduces the cellular ability to form immunological synapses with naïve CD4 T cells. Lamin A/C deletion induces alterations in NFκB nuclear localization, thereby influencing NFκB-dependent transcription. Furthermore, lamin A/C ablation modifies the epigenetic signature of BMDCs, predisposing these cells to mount a less effective antiviral response upon TLR stimulation. This study highlights the critical role of DCs in interacting with CD4 T cells during antiviral responses and elucidates the molecular mechanisms through which lamin A/C modulates DC function via epigenetic and transcriptional regulation.