IL18 signaling promotes homing of mature Tregs into the thymus.

Cristina Peligero-Cruz,Jakub Abramson,Yael Goldfarb,Francesco Roncato,Shir Nevo,Tal Givony,Arnau Sebé-Pedrós,Noam Kadouri,Ronen Alon,Jan Dobeš

doi:10.7554/elife.58213

Cristina Peligero-Cruz, Jakub Abramson + Show 8 more

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https://doi.org/10.7554/elife.58213

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Abstract

Foxp3+ regulatory T cells (Tregs) are potent suppressor cells, essential for the maintenance of immune homeostasis. Most Tregs develop in the thymus and are then released into the immune periphery. However, some Tregs populate the thymus and constitute a major subset of yet poorly understood cells. Here we describe a subset of thymus recirculating IL18R+ Tregs with molecular characteristics highly reminiscent of tissue-resident effector Tregs. Moreover, we show that IL18R+ Tregs are endowed with higher capacity to populate the thymus than their IL18R- or IL18R-/- counterparts, highlighting the key role of IL18R in this process. Finally, we demonstrate that IL18 signaling is critical for the induction of the key thymus-homing chemokine receptor - CCR6 on Tregs. Collectively, this study provides a detailed characterization of the mature Treg subsets in the mouse thymus and identifies a key role of IL18 signaling in controlling the CCR6-CCL20-dependent migration of Tregs into the thymus.

Highlights

forkhead box P3 (Foxp3)+CD25+CD4+ regulatory T cells (Tregs) are a suppressive T cell subset, essential for the maintenance of immune tolerance and homeostasis (Belkaid and Tarbell, 2009; Dominguez-Villar and Hafler, 2018; Josefowicz et al, 2012; Panduro et al, 2016; Sakaguchi et al, 2008)
Since recombination-activating gene 2 (Rag2) transcription is terminated upon positive selection in the thymus and green fluorescent protein (GFP) half-life is ~56 hr; the expression of GFP serves as a useful marker of T cell maturity following their positive selection (McCaughtry et al, 2007)
The thymus is a primary lymphoid organ, critical for the establishment of immunocompetent T lymphocytes, which are exported to the immune periphery for their safeguarding mission

Summary

Introduction

Foxp3+CD25+CD4+ regulatory T cells (Tregs) are a suppressive T cell subset, essential for the maintenance of immune tolerance and homeostasis (Belkaid and Tarbell, 2009; Dominguez-Villar and Hafler, 2018; Josefowicz et al, 2012; Panduro et al, 2016; Sakaguchi et al, 2008). Subsets of specialized Tregs have been described in various parenchymal tissues, including the muscle, lung, fat, skin, gut, or brain (Ali et al, 2017; Arpaia et al, 2015; Burzyn et al, 2013; Feuerer et al, 2009; Ito et al, 2019; Tanoue et al, 2016; Whibley et al, 2019) At these sites, Tregs perform functions beyond their conventional immunosuppressive roles, including regulation of tissue homeostasis, regeneration, and/or stem cell differentiation. Tregs were even shown to control insulin sensitivity (Bapat et al, 2015; Feuerer et al, 2009) or metabolic response to cold (Medrikova et al, 2015)

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