Therapeutically expanded human regulatory T-cells are super-suppressive due to HIF1A induced expression of CD73

Lorna B Jarvis,Hani S Mousa,Joanne L Jones,Luca Peruzzotti‐Jametti ,Fadi Issa,Daniel B Rainbow,Harpreet Kaur Mullay,John Q Davies ,Zoya Georgieva,Tom Ashmore,Aletta Van Den Bosch,Krishnaa Mahbubani ,Kourosh Saeb‐Parsy ,Sarah Howlett ,Julian L Griffin,Alasdair Coles ,﻿Stefano Pluchino ,Valerie Coppard,Linda S Wicker,James T Grist,Joanna Hester

doi:10.1038/s42003-021-02721-x

Abstract

The adoptive transfer of regulatory T-cells (Tregs) is a promising therapeutic approach in transplantation and autoimmunity. However, because large cell numbers are needed to achieve a therapeutic effect, in vitro expansion is required. By comparing their function, phenotype and transcriptomic profile against ex vivo Tregs, we demonstrate that expanded human Tregs switch their metabolism to aerobic glycolysis and show enhanced suppressive function through hypoxia-inducible factor 1-alpha (HIF1A) driven acquisition of CD73 expression. In conjunction with CD39, CD73 expression enables expanded Tregs to convert ATP to immunosuppressive adenosine. We conclude that for maximum therapeutic benefit, Treg expansion protocols should be optimised for CD39/CD73 co-expression.

Highlights

The adoptive transfer of regulatory T-cells (Tregs) is a promising therapeutic approach in transplantation and autoimmunity
Given the critical role Tregs play in controlling immune responses, there is a great deal of interest in their therapeutic potential, in the treatment of autoimmune diseases and in treating, or preventing, complications from transplantation, such as graft-versus-host disease (GvHD) following hematopoietic stem cell transplantation (HSCT), or graft rejection following solid organ transplantation
We demonstrate that stable CD73 expression occurs as expTregs switch their metabolism from oxidative phosphorylation (OXPHOS) to aerobic glycolysis, and that CD73 expression is driven by hypoxia-inducible factor 1-alpha (HIF1A)

Summary

Introduction

The adoptive transfer of regulatory T-cells (Tregs) is a promising therapeutic approach in transplantation and autoimmunity. Because large cell numbers are needed to achieve a therapeutic effect, in vitro expansion is required By comparing their function, phenotype and transcriptomic profile against ex vivo Tregs, we demonstrate that expanded human Tregs switch their metabolism to aerobic glycolysis and show enhanced suppressive function through hypoxia-inducible factor 1-alpha (HIF1A) driven acquisition of CD73 expression. Regulatory T cells (Tregs) are a subset of CD4+ T cells that play an indispensable role in maintaining self-tolerance and in controlling potentially harmful excessive immune responses to foreign antigens. They are characterized by surface expression of the high affinity IL-2 α-chain receptor (CD25), low expression of the IL-7 α-chain receptor (CD127) and by demethylation at a conserved region within intron 1 of the FOXP3 gene called the Treg-specific demethylated region (TSDR), leading to constitutive expression of their master transcription factor FOXP3. Given the clinical importance of optimizing their suppressive function, we suggest that therapeutic Treg expansion protocols should be optimized for CD39/CD73 co-expression

Methods

Results

Conclusion