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

Xuerui Zhang,Lulu Song,Jing Zhang,Zi-Chun Hua,Xinran Wang,Lina Huo,Peipei Xu,Zhaoqing Hu,Ying Wang,Yuheng Han

doi:10.3389/fimmu.2018.02038

Abstract

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.

Highlights

Intraepithelial lymphocytes (IELs), which are integral to the intestinal mucosal associated lymphoid system, play a key role in maintaining immune homeostasis of intestine
To determine at which point the differentiation of IELs was plagued by Fas-associated protein with death domain (FADD)-DN, we examined the lineage markers (Lin)− cells prepared from intestinal IELs and lamina propria lymphocytes (LPLs)
Analysis of Lin− IELs and Lin− LPLs revealed an arrest for CD8α+TCRγδ+ T development at stage of IL-7R−c-kit+Lin− LPLs in FADD-DN mice

Summary

Introduction

Intraepithelial lymphocytes (IELs), which are integral to the intestinal mucosal associated lymphoid system, play a key role in maintaining immune homeostasis of intestine. They constitute a constellation of barrier immune cells and contribute to the intestinal function by developing tolerance to food and microbial antigens in normal physiological state and controlling insults from pathogens and deleterious tissue inflammation during mucosal infections [1, 2]. The other bears CD8αα molecules and either TCRγδ or TCRαβ, which is present in the athymic mice These thymus-independent IELs like CD8αα+ T cells gather mainly in the intestinal mucosa and develop locally [3, 4]. There are striking differences in T cell differentiation process in the gut, when compared with T cell differentiation in the thymus, but far less is known about the molecules and signaling pathways that regulate the differentiation

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Results

Conclusion