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

The 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. (c) 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.