Rapid expansion of Treg cells protects from collateral colitis following a viral trigger

Michelle Schorer,Felix Rost,Katharina Lambert,Christian W Keller,Jan D Lünemann,Nicole Joller,Onur Boyman,Josua Oderbolz,Miro E Raeber,Alexander Yermanos,Roman Spörri,Gerhard Rogler,Nikolas Rakebrandt,Annette Oxenius,Kung-Chi Kao

doi:10.1038/s41467-020-15309-6

Abstract

Foxp3+ regulatory T (Treg) cells are essential for maintaining peripheral tolerance and preventing autoimmunity. While genetic factors may predispose for autoimmunity, additional environmental triggers, such as viral infections, are usually required to initiate the onset of disease. Here, we show that viral infection with LCMV results in type I IFN-dependent Treg cell loss that is rapidly compensated by the conversion and expansion of Vβ5+ conventional T cells into iTreg cells. Using Vβ5-deficient mice, we show that these Vβ5+ iTreg cells are dispensable for limiting anti-viral immunity. Rather, the delayed replenishment of Treg cells in Vβ5-deficient mice compromises suppression of microbiota-dependent activation of CD8+ T cells, resulting in colitis. Importantly, recovery from clinical symptoms in IBD patients is marked by expansion of the corresponding Vβ2+ Treg population in humans. Collectively, we provide a link between a viral trigger and an impaired Treg cell compartment resulting in the initiation of immune pathology.

Highlights

Foxp3+ regulatory T (Treg) cells are essential for maintaining peripheral tolerance and preventing autoimmunity
While these Vβ5+ induced Treg (iTreg) cells do not play a role in limiting the anti-viral immune response, they are essential for suppression of colitogenic CD8+ effector T cells at the gut barrier site
This role is fulfilled by Vβ2+ Treg cells, which are expanded in inflammatory bowel disease (IBD) patients with inactive disease

Summary

Introduction

Foxp3+ regulatory T (Treg) cells are essential for maintaining peripheral tolerance and preventing autoimmunity. We show that viral infection with LCMV results in type I IFN-dependent Treg cell loss that is rapidly compensated by the conversion and expansion of Vβ5+ conventional T cells into iTreg cells. Several autoimmune conditions, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and inflammatory bowel disease (IBD), are characterized by a relative loss of Treg cells or their functional impairment[4,5,6,7,8,9]. Our results show that the transient loss of Treg cells, mediated by type I IFNs, is rapidly compensated by induced Treg (iTreg) cells This Treg population is dominated by a single β chain TCR, Vβ5. We demonstrate that the virus-induced type I IFN response transiently compromises the Treg compartment and that a rapid compensation through conversion of Vβ5+ T cells into Treg cells is necessary to prevent autoimmune inflammation

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Conclusion