Analysis of T cell Repertoire and Transcriptome Identifies Mechanisms of Regulatory T cell (Treg) Suppression of GvHD

Abstract:

CD4+FOXP3+ regulatory T cells have demonstrated efficacy in graft-versus-host disease (GvHD) prevention and treatment. Preclinical and clinical studies indicate that Treg are able to protect from GvHD without interfering with the graft-versus-tumor (GvT) effect of hematopoietic cell transplantation (HCT), although the underlying molecular mechanisms are largely unknown. To elucidate Treg suppressive function during in vivo suppression of acute GvHD, the authors of this study published in Blood, led by Dr. Federico Simonetta (University of Geneva) and Pr. Robert S. Negrin (Stanford University), performed paired T cell receptor (TCRα, ΤCRβ genes) repertoire sequencing and RNA sequencing analysis on conventional T cells (Tcon) and Treg before and after transplantation in an MHC major-mismatch mouse model of HCT. They show that both Treg and Tcon underwent clonal restriction and that Treg did not interfere with the activation of alloreactive Tcon clones and the breadth of their TCR repertoire, however, markedly suppressed their expansion. Transcriptomic analysis revealed that Treg predominantly affected the transcriptome of CD4 Tcon and to a lesser extent of CD8 Tcon, modulating the transcription of genes encoding pro- and anti-inflammatory molecules as well as enzymes involved in metabolic processes, inducing a switch from glycolysis to oxidative phosphorylation. Finally, Treg did not interfere with the induction of gene sets involved in the GvT effect. These results shed light into the mechanisms of acute GvHD suppression by Treg and will support the clinical translation of this immunoregulatory approach.

Full article: https://doi.org/10.1182/blood.2022017982

Why is it important?

Allogeneic hematopoietic cell transplantation (HCT) is a procedure in which a patient receives healthy blood-forming cells (stem cells) and cells of the immune system to destroy tumor cells that may persist after chemotherapy. An allogeneic stem cell transplant is most often used to treat blood cancers, such as leukaemia, lymphoma, and certain blood or immune system disorders.

Unfortunately, allogeneic HCT is associated with significant morbidity and mortality related to cancer relapse and transplant complications, namely graft-versus-host disease (GvHD). There is a shared biology and a difficult separation of clinical graft-versus-tumour (GVT) effects from graft-versus-host disease (GVHD). Because of the interconnection between these two phenomena, none of the currently employed strategies for GvHD prevention and treatment can efficiently target GvHD without affecting GvT. 

The authors of this article, led by GCIR guest member Dr. Federico Simonetta (University of Geneva) and Pr. Robert S. Negrin (Stanford University), previously showed in preclinical mouse models that regulatory T cells (Treg) are able to protect from GvHD without interfering with the GvT effect of HCT. In this study, they show that Treg qualitatively modulate conventional T-cell function through several mechanisms rather than preventing the activation of alloreactive clones, providing a potential explanation for the ability of Treg to suppress GvHD while allowing GvT. These results will help the improvement of immunoregulatory cellular therapies for GvHD prevention and treatment.

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