Analysis of the T-cell repertoire and transcriptome identifies mechanisms of regulatory T-cell suppression of GVHD

• Published in: Blood 2023-04, Vol.141 (14), p.1755-1767
• Main Authors: Lohmeyer, Juliane K., Hirai, Toshihito, Turkoz, Mustafa, Buhler, Stephane, Lopes Ramos, Teresa, Köhler, Natalie, Baker, Jeanette, Melotti, Astrid, Wagner, Ingrid, Pradier, Amandine, Wang, Sisi, Ji, Xuhuai, Becattini, Simone, Villard, Jean, Merkler, Doron, Chalandon, Yves, Negrin, Robert S., Simonetta, Federico
• Format: Article
• Language: English
• Subjects: Animals; Graft vs Host Disease - genetics; Graft vs Host Disease - pathology; Graft vs Host Disease - prevention & control; Hematopoietic Stem Cell Transplantation; Mice; Proteins - genetics; T-Lymphocytes, Regulatory - pathology; Transcriptome
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.2022017982

•Regulatory T cells modulate Tcon transcriptome during GVHD suppression by affecting several nonredundant pathways.•Regulatory T cells undergo activation and clonal expansion during GVHD suppression. [Display omitted] CD4+FOXP3+ regulatory T cells (Tregs) have demonstrated efficacy in the prevention and treatment of graft-versus-host disease (GVHD). Preclinical and clinical studies indicate that Tregs 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, we performed paired T-cell receptor (TCRα and ΤCRβ genes) repertoire sequencing and RNA sequencing analysis on conventional T cells (Tcons) and Tregs before and after transplantation in a major histocompatibility complex –mismatched mouse model of HCT. We show that both Tregs and Tcons underwent clonal restriction, and Tregs did not interfere with the activation of alloreactive Tcon clones and the breadth of their TCR repertoire but markedly suppressed their expansion. Transcriptomic analysis revealed that Tregs predominantly affected the transcriptome of CD4 Tcons and, to a lesser extent, that of CD8 Tcons, thus 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, Tregs did not interfere with the induction of gene sets involved in the GVT effect. Our results shed light onto the mechanisms of acute GVHD suppression by Tregs and will support the clinical translation of this immunoregulatory approach. Infusion of regulatory T cells (Tregs) is emerging as a clinically attractive, but still poorly understood, approach to mitigate graft-versus-host disease (GVHD). Lohmeyer and colleagues used murine models to reveal how Tregs affect the transcriptomic, metabolic, and functional state of pathogenic effector T cells, thereby blunting GVHD after allogeneic hematopoietic cell transplantation. Tregs undergo activation and clonal expansion during GVHD suppression and do not interfere with the induction of genes associated with tumor control, features that can be further exploited therapeutically.