부산대학교 도서관

Keywords: CD4.sup.+ T-cells; inflammatory bowel disease; FOXP3; lamin A/C; regulatory T-cell Abstract The mechanisms by which lamin A/C in CD4.sup.+ 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.sup.-/- mice of Lmna.sup.-/- CD4.sup.+ 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.sup.+ 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.sup.+ dendritic cells downregulated lamin A/C in CD4.sup.+ T-cells, enhancing Treg differentiation. However, non-RA-producing CD103.sup.- dendritic cells predominated in peripheral lymph nodes, facilitating lamin A/C expression in CD4.sup.+ 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. CAPTION(S): Supplementary materials and methods Supplementary figure legends Figure S1. GFP-lamin A/C retrovirus drives lamin A/C overexpression Figure S2. Lmna-/- CD4+ T-cells show increased Ezh1 and reduced Eed mRNA levels Figure S3. FOXP3 downregulation reduces GITR membrane expression in Lmna-/- and WT CD4+ T-cells Figure S4. A-type lamin deficiency in CD4+ T-cells protects against IBD development in mice Figure S5. Retinoic acid (RA) downregulates lamin A/C in CD4+ T-cells Figure S6. Expression of retinoic acid receptor [alpha], [beta], and [gamma] in naive, activated, and Treg differentiated CD4 T-cells and stimulation of RAR[alpha] or RAR[gamma] reduces lamin A/C protein induction upon CD4 T-cell stimulation Figure S7. Lamin A/C downregulation augments Treg differentiation in vitro and in vivo and provides equal protection against IBD as retinoic acid (RA) treatment Table S1. Primers used for ChIP-qPCR analysis Table S2. Primers used for RT-qPCR analysis (mentioned in supplementary material, Supplementary materials and methods) Byline: Raquel Toribio-Fernandez,Beatriz Herrero-Fernandez, Virginia Zorita, Juan A Lopez, Jesus Vazquez, Gabriel Criado, Jose L Pablos, Philippe Collas, Francisco Sanchez-Madrid, Vicente Andres,Jose M Gonzalez-Granado