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Dominant Negative FADD/MORT1 Inhibits the Development of Intestinal Intraepithelial Lymphocytes With a Marked Defect on CD8αα+TCRγδ+ T Cells

Intestinal intraepithelial lymphocytes (IELs) play a critical role in mucosal immune system, which differ from thymus-derived cells and develop locally in gut. Although the development of IELs has been studied in some detail, the molecular cues controlling their local development remain unclear. Her...

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Autores principales: Zhang, Xuerui, Huo, Lina, Song, Lulu, Hu, Zhaoqing, Wang, Xinran, Han, Yuheng, Wang, Ying, Xu, Peipei, Zhang, Jing, Hua, Zi-Chun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6139313/
https://www.ncbi.nlm.nih.gov/pubmed/30250469
http://dx.doi.org/10.3389/fimmu.2018.02038
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author Zhang, Xuerui
Huo, Lina
Song, Lulu
Hu, Zhaoqing
Wang, Xinran
Han, Yuheng
Wang, Ying
Xu, Peipei
Zhang, Jing
Hua, Zi-Chun
author_facet Zhang, Xuerui
Huo, Lina
Song, Lulu
Hu, Zhaoqing
Wang, Xinran
Han, Yuheng
Wang, Ying
Xu, Peipei
Zhang, Jing
Hua, Zi-Chun
author_sort Zhang, Xuerui
collection PubMed
description Intestinal intraepithelial lymphocytes (IELs) play a critical role in mucosal immune system, which differ from thymus-derived cells and develop locally in gut. Although the development of IELs has been studied in some detail, the molecular cues controlling their local development remain unclear. Here, we demonstrate that FADD, a classic adaptor protein required for death-receptor-induced apoptosis, is a critical regulator of the intestinal IEL development. The mice with a dominant negative mutant of FADD (FADD-DN) display an abnormal development of intestinal IELs with a marked reduction in the numbers of CD8αα(+)TCRγδ(+) T cells. As a precursor for CD8αα(+) development, lamina propria lymphocytes in lin-negative expression (lin(−) LPLs) were analyzed and the massive accumulation of IL-7R(−)lin(−) LPLs was observed in FADD-DN mice. As IL-7R is one of Notch1-target genes, we further observed that the level of Notch1 expression was lower in Lin(−) LPLs from FADD-DN mice compared with normal mice. The downregulation of Notch1 expression induced by FADD-DN overexpression was also confirmed in Jurkat T cells. Considering that IL-7 and its receptor IL7-R play a differentiation inducing role in the development of intestinal IELs, the influence of FADD via its DD domain on Notch1 expression might be a possible molecular signal involved in the early IELs development. In addition, loss of γδ T-IELs in FADD-DN mice aggravates DSS-induced colitis, suggesting that FADD is a relevant contribution to the field of mucosal immunology and intestinal homeostasis.
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spelling pubmed-61393132018-09-24 Dominant Negative FADD/MORT1 Inhibits the Development of Intestinal Intraepithelial Lymphocytes With a Marked Defect on CD8αα+TCRγδ+ T Cells Zhang, Xuerui Huo, Lina Song, Lulu Hu, Zhaoqing Wang, Xinran Han, Yuheng Wang, Ying Xu, Peipei Zhang, Jing Hua, Zi-Chun Front Immunol Immunology Intestinal intraepithelial lymphocytes (IELs) play a critical role in mucosal immune system, which differ from thymus-derived cells and develop locally in gut. Although the development of IELs has been studied in some detail, the molecular cues controlling their local development remain unclear. Here, we demonstrate that FADD, a classic adaptor protein required for death-receptor-induced apoptosis, is a critical regulator of the intestinal IEL development. The mice with a dominant negative mutant of FADD (FADD-DN) display an abnormal development of intestinal IELs with a marked reduction in the numbers of CD8αα(+)TCRγδ(+) T cells. As a precursor for CD8αα(+) development, lamina propria lymphocytes in lin-negative expression (lin(−) LPLs) were analyzed and the massive accumulation of IL-7R(−)lin(−) LPLs was observed in FADD-DN mice. As IL-7R is one of Notch1-target genes, we further observed that the level of Notch1 expression was lower in Lin(−) LPLs from FADD-DN mice compared with normal mice. The downregulation of Notch1 expression induced by FADD-DN overexpression was also confirmed in Jurkat T cells. Considering that IL-7 and its receptor IL7-R play a differentiation inducing role in the development of intestinal IELs, the influence of FADD via its DD domain on Notch1 expression might be a possible molecular signal involved in the early IELs development. In addition, loss of γδ T-IELs in FADD-DN mice aggravates DSS-induced colitis, suggesting that FADD is a relevant contribution to the field of mucosal immunology and intestinal homeostasis. Frontiers Media S.A. 2018-09-10 /pmc/articles/PMC6139313/ /pubmed/30250469 http://dx.doi.org/10.3389/fimmu.2018.02038 Text en Copyright © 2018 Zhang, Huo, Song, Hu, Wang, Han, Wang, Xu, Zhang and Hua. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Zhang, Xuerui
Huo, Lina
Song, Lulu
Hu, Zhaoqing
Wang, Xinran
Han, Yuheng
Wang, Ying
Xu, Peipei
Zhang, Jing
Hua, Zi-Chun
Dominant Negative FADD/MORT1 Inhibits the Development of Intestinal Intraepithelial Lymphocytes With a Marked Defect on CD8αα+TCRγδ+ T Cells
title Dominant Negative FADD/MORT1 Inhibits the Development of Intestinal Intraepithelial Lymphocytes With a Marked Defect on CD8αα+TCRγδ+ T Cells
title_full Dominant Negative FADD/MORT1 Inhibits the Development of Intestinal Intraepithelial Lymphocytes With a Marked Defect on CD8αα+TCRγδ+ T Cells
title_fullStr Dominant Negative FADD/MORT1 Inhibits the Development of Intestinal Intraepithelial Lymphocytes With a Marked Defect on CD8αα+TCRγδ+ T Cells
title_full_unstemmed Dominant Negative FADD/MORT1 Inhibits the Development of Intestinal Intraepithelial Lymphocytes With a Marked Defect on CD8αα+TCRγδ+ T Cells
title_short Dominant Negative FADD/MORT1 Inhibits the Development of Intestinal Intraepithelial Lymphocytes With a Marked Defect on CD8αα+TCRγδ+ T Cells
title_sort dominant negative fadd/mort1 inhibits the development of intestinal intraepithelial lymphocytes with a marked defect on cd8αα+tcrγδ+ t cells
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6139313/
https://www.ncbi.nlm.nih.gov/pubmed/30250469
http://dx.doi.org/10.3389/fimmu.2018.02038
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