Interleukin-7 Links T Lymphocyte and Intestinal Epithelial Cell Homeostasis

Shabnam Shalapour,Daniela Finke,Markus M Heimesaat,Michael Fromm,Günter J Hämmerling,Rainer Glauben,Anja A Kühl,André Fischer,Bernd Arnold,Özen Sercan,Thomas Schüler,Susanne M Krug,Christoph Loddenkemper,Katrin Deiser,Britta Siegmund,Stefan Bereswill,Stephane Chappaz,Hang Thi Thu Nguyen

doi:10.1371/journal.pone.0031939

Abstract

Interleukin-7 (IL-7) is a major survival factor for mature T cells. Therefore, the degree of IL-7 availability determines the size of the peripheral T cell pool and regulates T cell homeostasis. Here we provide evidence that IL-7 also regulates the homeostasis of intestinal epithelial cells (IEC), colon function and the composition of the commensal microflora. In the colon of T cell-deficient, lymphopenic mice, IL-7-producing IEC accumulate. IEC hyperplasia can be blocked by IL-7-consuming T cells or the inactivation of the IL-7/IL-7R signaling pathway. However, the blockade of the IL-7/IL-7R signaling pathway renders T cell-deficient mice more sensitive to chemically-induced IEC damage and subsequent colitis. In summary, our data demonstrate that IL-7 promotes IEC hyperplasia under lymphopenic conditions. Under non-lymphopenic conditions, however, T cells consume IL-7 thereby limiting IEC expansion and survival. Hence, the degree of IL-7 availability regulates both, T cell and IEC homeostasis.

Highlights

Interleukin-7 (IL-7) is a crucial survival factor for T cells and the competition for IL-7 is the major regulatory principle that stabilizes peripheral T cell homeostasis [1,2]
Lymphopenia-associated intestinal epithelial cells (IEC) hyperplasia leads to the accumulation of IL-7+ cells
CD4+ T cells recognizing antigens derived from the commensal microflora cause colitis under lymphopenic conditions [26]

Summary

Introduction

Interleukin-7 (IL-7) is a crucial survival factor for T cells and the competition for IL-7 is the major regulatory principle that stabilizes peripheral T cell homeostasis [1,2]. The lack of IL-7consuming T cells is associated with increased levels of serum IL-7 in lymphopenic humans and mice [4,5]. Elevated levels of IL-7 promote spontaneous T cell activation [7] and T cell-mediated inflammation in the intestine and other organs [8,9,10]. The overabundance of IL-7 under lymphopenic conditions contributes to the activation of adoptively transferred, naıve T lymphocytes, which undergo lymphopenia-induced proliferation (LIP), convert into effector/memory T cells and cause inflammation in the large intestine [11,12]. Based on the aforementioned observations, the blockade of IL-7R signaling in pathogenic T cells is considered as a therapeutic option for the treatment of T cell-mediated autoimmunity [13,14]

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Results

Conclusion