Affordable Access

deepdyve-link
Publisher Website

Operational tolerance after hematopoietic stem cell transplantation is characterized by distinct transcriptional, phenotypic, and metabolic signatures

Authors
  • Dubouchet, Laetitia
  • Todorov, Helena
  • Seurinck, Ruth
  • Vallet, Nicolas
  • Van Gassen, Sofie
  • Corneau, Aurélien
  • Blanc, Catherine
  • Zouali, Habib
  • Boland, Anne
  • Deleuze, Jean-François
  • Ingram, Brian
  • de Latour, Regis Peffault
  • Saeys, Yvan
  • Socié, Gérard
  • Michonneau, David
Publication Date
Feb 23, 2022
Identifiers
DOI: 10.1126/scitranslmed.abg3083
PMID: 35196024
OAI: oai:HAL:hal-03599282v1
Source
HAL
Keywords
Language
English
License
Unknown
External links

Abstract

The mechanisms underlying operational tolerance after hematopoietic stem cell transplantation in humans are poorly understood. We studied two independent cohorts of patients who underwent allogeneic hematopoietic stem cell transplantation from human leukocyte antigen–identical siblings. Primary tolerance was associated with long-lasting reshaping of the recipients’ immune system compared to their healthy donors with an increased proportion of regulatory T cell subsets and decreased T cell activation, proliferation, and migration. Transcriptomics profiles also identified a role for nicotinamide adenine dinucleotide biosynthesis in the regulation of immune cell functions. We then compared individuals with operational tolerance and nontolerant recipients at the phenotypic, transcriptomic, and metabolomic level. We observed alterations centered on CD38 + -activated T and B cells in nontolerant patients. In tolerant patients, cell subsets with regulatory functions were prominent. RNA sequencing analyses highlighted modifications in the tolerant patients’ transcriptomic profiles, particularly with overexpression of the ectoenzyme NT5E (encoding CD73), which could counterbalance CD38 enzymatic functions by producing adenosine. Further, metabolomic analyses suggested a central role of androgens in establishing operational tolerance. These data were confirmed using an integrative approach to evaluating the immune landscape associated with operational tolerance. Thus, balance between a CD38-activated immune state and CD73-related production of adenosine may be a key regulator of operational tolerance.

Report this publication

Statistics

Seen <100 times