CD27 expression on Treg cells limits immune responses against tumors

Sabine Muth,Hansjörg Schild,Hans Christian Probst,Markus Radsak,Annekatrin Klaric

doi:10.1007/s00109-021-02116-9

Abstract

Regulatory T cells (Tregs) suppress immune responses and thus contribute to immune homeostasis. On the downside, Tregs also limit immune responses against tumors promoting the progression of cancer. Among the many mechanisms implied in Treg-mediated suppression, the inhibition of dendritic cells (DCs) has been shown to be central in peripheral tolerance induction as well as in cancers. We have shown previously that the maintenance of peripheral T cell tolerance critically depends on cognate interactions between Tregs and DCs and that the CTL priming by unsuppressed steady state DCs is mediated via CD70. Here, we have investigated whether the CD70/CD27 axis is also involved in Treg-mediated suppression of anti-tumor immunity. Using a mixed bone marrow chimeric mouse model in which we can deplete regulatory T cells in a temporally controlled fashion, we show that Treg-expressed CD27 prevents the breakdown of peripheral tolerance and limits anti-tumor immunity. Furthermore, ablation of Treg expressed CD27 acts synergistically with PD-1 checkpoint inhibition to improve CTL mediated immunity against a solid tumor. Our data thus identify Treg-expressed CD27 as a potential target in cancer immunotherapy.Key messagesTreg expressed CD27 maintains steady state DC tolerogenicTreg expressed CD27 limits anti-tumor immunityAblation of Treg expressed CD27 synergizes with PD-1 blockade to improve CTL mediated tumor control

Highlights

Immune suppression by C D4+CD25+ FoxP3+ regulatory T cells (Treg) is indispensable for the maintenance of peripheral tolerance
Journal of Molecular Medicine mouse model in which transgenic cytotoxic T lymphocyte (CTL) epitope expression can be induced selectively on dendritic cells (DC) [11], we have shown that Treg depletion leads to a functional activation of dendritic cells resulting in priming of naive T cells instead of peripheral tolerance induction [12]
When we investigated the mechanisms that are involved in the breakdown of peripheral tolerance upon Treg depletion, we found that unsuppressed steady state DCs prime CTLs in a CD70-dependent manner

Summary

Introduction

Immune suppression by C D4+CD25+ FoxP3+ regulatory T cells (Treg) is indispensable for the maintenance of peripheral tolerance. The suppression of dendritic cell activation by Treg cells thereby critically depends on direct TCR-MHC class II interactions between Tregs and DCs. DCs that lack MHC class II expression and cannot make cognate interactions with Treg cells show an activated phenotype and are completely unable to induce peripheral CD8+ T-cell tolerance resulting in the development of fatal, CTL mediated autoimmunity [13]. When we investigated the mechanisms that are involved in the breakdown of peripheral tolerance upon Treg depletion, we found that unsuppressed steady state DCs prime CTLs in a CD70-dependent manner. The functional role of this pathway for the suppression of autoreactive CTL and immune responses against malignant cells remains undefined

Methods

Results

Conclusion