Regulatory T Cells Inhibit T Cell Activity by Downregulating CD137 Ligand via CD137 Trogocytosis.

Khang Luu,Herbert Schwarz,Stina L. Wickström,Mugdha Vijay Patwardhan,Andreas Lundqvist,Qun Zeng

doi:10.3390/cells10020353

Khang Luu, Herbert Schwarz + Show 4 more

Open Access

https://doi.org/10.3390/cells10020353

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Journal: Cells	Publication Date: Feb 9, 2021
Citations: 7	License type: CC BY 4.0

Affiliation: National University of Singapore, Karolinska Institutet

Abstract

CD137 is a costimulatory molecule expressed on activated T cells. CD137 ligand (CD137L) is expressed by antigen presenting cells (APC), which use the CD137—CD137L system to enhance immune responses. It was, therefore, surprising to discover CD137 expression on regulatory T cells (Treg). The function of CD137 in Treg are controversial. While some studies report that CD137 signalling converts Treg to effector T cells (Teff), other studies find that CD137-expressing Treg display a stronger inhibitory activity than CD137- Treg. Here, we describe that CD137 on Treg binds to CD137L on APC, upon which one of the two molecules is transferred via trogocytosis to the other cell, where CD137—CD137L forms a complex that is internalized and deprives APC of the immune-stimulatory CD137L. Truncated forms of CD137 that lack the cytoplasmic domain of CD137 are also able to downregulate CD137L, demonstrating that CD137 signalling is not required. Comparable data have been obtained with human and murine cells, indicating that this mechanism is evolutionarily conserved. These data describe trogocytosis of CD137 and CD137L as a new mechanism employed by Treg to control immune responses by downregulating the immunostimulatory CD137L on APC.

Highlights

The costimulatory molecule CD137 is a main driver for cellular immune responses.Cross-linking of CD137 strongly enhances proliferation, IFN-γ secretion, and the cytolytic activity of T cells
When murine Treg were cocultured with RAW264.7 cells, CD137 levels on Treg decreased, and this decrease was dependent on the presence of CD137 ligand (CD137L) as shown by the comparison of Treg in cocultures with WT RAW264.7 or CD137L−/− RAW cells (Figure 1B)
To ascertain that the observed downregulation of CD137L is due to CD137 expression, we cocultured WT RAW264.7 cells with WT Treg or CD137-deficient (CD137−/−) Treg, which were isolated from spleens of WT mice or CD137−/− mice, respectively

Summary

Introduction

The costimulatory molecule CD137 is a main driver for cellular immune responses.Cross-linking of CD137 strongly enhances proliferation, IFN-γ secretion, and the cytolytic activity of T cells. The costimulatory molecule CD137 is a main driver for cellular immune responses. Given that CD137 signalling is a potent driver of cellular immune responses, it is surprising to find strong expression of CD137 on Teff and on Treg. Human and murine Tregs that had infiltrated tumours, expressed high amounts of CD137 [8] and a high frequency of CD137+ Treg correlated with poor prognosis in lung adenocarcinoma patients [9]. This is in line with CD137+ Treg being more suppressive than CD137- Treg [10,11]. Not clear how CD137 expression helps Treg to become more suppressive

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