Interleukin 4 promotes the development of ex-Foxp3 Th2 cells during immunity to intestinal helminths.

Victoria S Pelly,Judith E Allen,Manolis Gialitakis,Stephanie Czieso,Isobel S Okoye,Dominik Rückerl,Frank Brombacher,Lewis J Entwistle,Jimena Perez-Lloret,Mark S Wilson,Yashaswini Kannan,Stephanie M Coomes

doi:10.1084/jem.20161104

Abstract

Immunity to intestinal helminth infections requires the rapid activation of T helper 2 cells (Th2 cells). However, simultaneous expansion of CD4+Foxp3+ regulatory T cells (T reg cells) impedes protective responses, resulting in chronic infections. The ratio between T reg and effector T cells can therefore determine the outcome of infection. The redifferentiation of T reg cells into Th cells has been identified in hyperinflammatory diseases. In this study, we asked whether ex-T reg Th2 cells develop and contribute to type-2 immunity. Using multigene reporter and fate-reporter systems, we demonstrate that a significant proportion of Th2 cells derive from Foxp3+ cells after Heligmosomoides polygyrus infection and airway allergy. Ex-Foxp3 Th2 cells exhibit characteristic Th2 effector functions and provide immunity to H. polygyrus Through selective deletion of Il4ra on Foxp3+ cells, we further demonstrate IL-4 is required for the development of ex-Foxp3 Th2 cells. Collectively, our findings indicate that converting T reg cells into Th2 cells could concomitantly enhance Th2 cells and limit T reg cell-mediated suppression.

Highlights

A heterogeneous population of regulatory T cells (T reg cells) is required to maintain immune homeostasis and limit excessive immune responses to infection (Belkaid, 2007; Campbell and Koch, 2011)
Distinct immune pathways have been shown to be involved in immunity to H. polygyrus, such as increased intestinal inflammation (Fig. 1 C, Hematoxylin and eosin (H&E)), mucus (Fig. 1 C, Alcian blue–periodic acid–Schiff (AB-PAS)), and goblet cell–derived Relmβ (Retnlb) secretion and the alternative activation of macrophages (AAMΦ; Arg1, Retnla, and Chil3; Fig. 1 D; Urban et al, 1991a;Anthony et al, 2006; Herbert et al, 2009)
It has recently emerged that T reg cells are heterogeneous, with T reg cell–mediated immune homeostasis requiring a degree of specialization for migration to unique environments and for targeting distinct immune cell subsets (Campbell and Koch, 2011)

Summary

Introduction

A heterogeneous population of regulatory T cells (T reg cells) is required to maintain immune homeostasis and limit excessive immune responses to infection (Belkaid, 2007; Campbell and Koch, 2011). Protection from immune-mediated pathology and autoimmunity can permit the establishment of chronic infections (Gause et al, 2013). After a primary infection with the natural mouse parasite Heligmosomoides polygyrus, the early expansion (Grainger et al, 2010) and activation (Finney et al, 2007) of Foxp3-expressing T reg cells limits excessive T helper 2 cell (Th2 cell) responses and immunopathology, resulting in the establishment of chronic infections (Rausch et al, 2009).

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