Journal
JOURNAL OF PATHOLOGY
Volume 249, Issue 4, Pages 509-522Publisher
WILEY
DOI: 10.1002/path.5332
Keywords
CD4(+) T-cells; inflammatory bowel disease; FOXP3; lamin A; C; regulatory T-cell
Funding
- Research Council of Norway
- ISCIII [PI14/00526, PI17/01395, CP11/00145, CPII16/00022, RD12/0042/0028, PI16/00032, RETICs RD16/0012 RIER]
- ISCIII (EuroCellNet COST Action) [CA15214]
- Miguel Servet Program
- Fundacion Ramon Areces
- Spanish Ministry of Economy and Competitiveness (MINECO) [SAF2013-46663-R, SAF2016-79490-R]
- MINECO [SAF2017-82886-R, BIO2015-67580-P]
- European Research Council [ERC-2011-AdG 294340-GENTRIS]
- ISCIII (CIBER CARDIOVASCULAR) [PIE 13.0004-BIOIMID]
- Comunidad Autonoma de Madrid [CAM-B2017/BMD-3671-INFLAMUNE]
- ISCIII(PRB3) [IPT17/0019 ISCIII-SGEFI/ERDF]
- European Regional Development Fund (ERDF) 'Una manera de hacer Europa'
- Instituto de Salud Carlos III (ISCIII)
- Ministerio de Ciencia, Innovacion y Universidades (MCNU)
- Pro CNIC Foundation
- Instituto de Investigacion Hospital 12 de Octubre (i+ 12)
- ISCIII Miguel Servet Program
- i+ 12
- Universidad Autonoma de Madrid (UAM)
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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.
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