Tissue-Restricted Adaptive Type 2 Immunity Is Orchestrated by Expression of the Costimulatory Molecule OX40L on Group 2 Innate Lymphoid Cells

Timotheus Y.F Halim,Batika M.J Rana,Jennifer A Walker,Bernhard Kerscher,Martin D Knolle,Helen E Jolin,Eva M Serrao,Liora Haim-Vilmovsky,Sarah A Teichmann,Hans-Reimer Rodewald,Marina Botto,Timothy J Vyse,Padraic G Fallon,Zhi Li,David R Withers,Andrew N.J Mckenzie

doi:10.1016/j.immuni.2018.05.003

Abstract

SummaryThe local regulation of type 2 immunity relies on dialog between the epithelium and the innate and adaptive immune cells. Here we found that alarmin-induced expression of the co-stimulatory molecule OX40L on group 2 innate lymphoid cells (ILC2s) provided tissue-restricted T cell co-stimulation that was indispensable for Th2 and regulatory T (Treg) cell responses in the lung and adipose tissue. Interleukin (IL)-33 administration resulted in organ-specific surface expression of OX40L on ILC2s and the concomitant expansion of Th2 and Treg cells, which was abolished upon deletion of OX40L on ILC2s (Il7raCre/+Tnfsf4fl/fl mice). Moreover, Il7raCre/+Tnfsf4fl/fl mice failed to mount effective Th2 and Treg cell responses and corresponding adaptive type 2 pulmonary inflammation arising from Nippostrongylus brasiliensis infection or allergen exposure. Thus, the increased expression of OX40L in response to IL-33 acts as a licensing signal in the orchestration of tissue-specific adaptive type 2 immunity, without which this response fails to establish.

Highlights

Type 2 immunity underpins numerous key homeostatic and immune processes in health and disease (Pulendran and Artis, 2012)
While adaptive type 2 immune cells are rare in most tissues under homeostatic conditions, innate group 2 innate lymphoid cells (ILC2s) are tissue-resident cells and rapidly respond to type 2 alarmins by producing factors shared with both T helper 2 (Th2) (IL-5 and IL-13) and Treg (Amphiregulin) cell function
ILC2 Are Critical for Regulating Adaptive Type 2 Immunity Airway exposure to the protease allergen papain results in IL-33dependent accumulation of GATA3+ ILC2s and Th2 cells

Summary

Introduction

Type 2 immunity underpins numerous key homeostatic and immune processes in health and disease (Pulendran and Artis, 2012). The type 2 cytokine environment is regulated at the tissue level by the release of epithelium-derived type 2 cytokines, including interleukin (IL)-25, thymic stromal lymphopoietin (TSLP), and the alarmin IL-33. These molecules elicit the production of type 2 effector cytokines from immune cells, which are fundamental for diverse functions, ranging from anti-helminth parasite immunity to allergic inflammation, wound healing responses, and metabolism (Gause et al, 2013; Man et al, 2017). CD4+ regulatory T (Treg) cells are increasingly associated with some type 2 inflammatory functions, such as wound healing and adipose tissue homeostasis (Odegaard and Chawla, 2015; Panduro et al, 2016). The division of labor, and interactions, between ILC2s and adaptive type 2 immune cells remains a fundamental and unresolved question

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