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

J Pathol. 2019 Dec;249(4):509-522. doi: 10.1002/path.5332. Epub 2019 Oct 30.

Abstract

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. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Keywords: CD4+ T-cells; FOXP3; inflammatory bowel disease; lamin A/C; regulatory T-cell.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Animals
  • Cell Differentiation*
  • Colitis / immunology
  • Colitis / metabolism
  • Colitis / pathology
  • Colitis / prevention & control*
  • Colon / immunology
  • Colon / metabolism*
  • Colon / pathology
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Disease Models, Animal
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Lamin Type A / deficiency*
  • Lamin Type A / genetics
  • Lymph Nodes / immunology
  • Lymph Nodes / metabolism
  • Mice, Knockout
  • Signal Transduction
  • T-Box Domain Proteins / genetics
  • T-Box Domain Proteins / metabolism
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / metabolism*
  • T-Lymphocytes, Regulatory / transplantation
  • Th1 Cells / immunology
  • Th1 Cells / metabolism*
  • Tretinoin / metabolism

Substances

  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Homeodomain Proteins
  • Lamin Type A
  • Lmna protein, mouse
  • T-Box Domain Proteins
  • T-box transcription factor TBX21
  • RAG-1 protein
  • Tretinoin