Lamin A/C deficiency in CD4+ T‐cells enhances regulatory T‐cells and prevents inflammatory bowel disease

• DOI: 10.1002/path.5332
• Publication Date: 2019-08-02T10:44:51Z
• Authors: Raquel Toribio‐Fe...; Beatriz Herrero‐F...; Virginia Zorita; Juan A López; Jesús Vázquez; Gabriel Criado; Jose L Pablos; Philippe Collas; Francisco Sánchez...; Vicente Andrés; Jose M Gonzalez‐G...
• Keywords: Homeodomain Proteins; Mice, Knockout; 0301 basic medicine; 0303 health sciences; Colon; Cell Differentiation; Forkhead Transcription Factors; Tretinoin; Dendritic Cells; Th1 Cells; Colitis; Lamin Type A; Adoptive Transfer; T-Lymphocytes, Regulatory; 3. Good health; Disease Models, Animal; 03 medical and health sciences; Animals; Lymph Nodes; T-Box Domain Proteins; Signal Transduction

AbstractThe mechanisms by which lamin A/C in CD4+ T‐cells control intestinal homeostasis and can cause inflammatory bowel disease (IBD) are unknown. Here, we explore lamin A/C in a mouse model of IBD. Adoptive transfer to Rag1−/− mice of Lmna−/− CD4+ T‐cells, which have enhanced regulatory T‐cells (Treg) differentiation and function, induced less severe IBD than wild‐type T‐cells. Lamin A/C deficiency in CD4+ T‐cells enhanced transcription of the Treg master regulator FOXP3, thus promoting Treg differentiation, and reduced Th1 polarization, due to epigenetic changes in the Th1 master regulator T‐bet. In mesenteric lymph nodes, retinoic acid (RA) released by CD103+ dendritic cells downregulated lamin A/C in CD4+ T‐cells, enhancing Treg differentiation. However, non‐RA‐producing CD103− dendritic cells predominated in peripheral lymph nodes, facilitating lamin A/C expression in CD4+ T‐cells and therefore Th1 differentiation. Our findings establish lamin A/C as a key regulator of Th differentiation in physiological conditions and show it as a potential immune‐regulatory target in IBD. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.