Nr4a Receptors Regulate Development and Death of Labile Treg Precursors to Prevent Generation of Pathogenic Self-Reactive Cells

Takashi Sekiya,Sana Hibino,Keita Saeki,Mitsuhiro Kanamori,Satoshi Takaki,Akihiko Yoshimura

doi:10.1016/j.celrep.2018.07.008

Takashi Sekiya, Sana Hibino + Show 4 more

Open Access

https://doi.org/10.1016/j.celrep.2018.07.008

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Abstract

Regulatory T (Treg) cells develop from a self-reactive, CD4-single positive (CD4SP) precursor cell pool. Thus, Treg-fated developing thymocytes are expected to possess the potential to generate pathogenic self-reactive cells. However, no such pathogenic conversion has been observed, indicating mechanisms of defense to prevent such a deleterious event. Here, we show that, after the initial developmental phase, the Nr4a family of nuclear receptors promotes the development of Treg cells by cooperating with other Treg cell developmental machineries, as well as by forming a reinforcing loop with Foxp3. Nr4a-deficient Treg-fated thymocytes survive and can elicit autoimmunity, highlighting their roles in elimination of developing Treg precursors that fail to complete their development. Our findings reveal that the defective development of Treg-fated thymocytes is a potential route for the generation of pathogenic self-reactive cells, which is normally suppressed by Nr4a factors at both developmental and cell death levels.

Highlights

The tolerance of CD4+T cells to self-antigens depends largely on their fate decision, which occurs during their development in the thymus
Our findings reveal a potential route for the generation of pathogenic self-reactive cells from the thymus: the defective development of Treg cells (Tregs)-fated thymocytes and their eventual escape from elimination, both of these processes are normally strictly suppressed by Nr4a factors
The Nr4a-TKO CD25hiGITRhi CD4-SP thymocytes were expected to comprise a mixture of Treg-precursors and ‘‘abolished’’ Tregs that failed to complete development to mature Tregs

Summary

Introduction

The tolerance of CD4+T cells to self-antigens depends largely on their fate decision, which occurs during their development in the thymus. Impaired negative selection in the thymus may be a major source of such self-reactive pathogenic cells. Escape of potentially pathogenic self-reactive CD4+T cells from negative selection process is thought to routinely occur at low levels even in normal individuals. This escape can be further accelerated by disruption of any of several machineries that mediate negative selection. Impairment of either the presentation of self-antigens or the elimination of self-reactive thymocytes generates pathogenic self-reactive CD4+T cells from the thymus and eventually results in autoimmunity (Bouillet et al, 1999; DeVoss et al, 2006)

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