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

Article Article scientifique Article Operational tolerance after hematopoietic stem cell transplantation is characterized by distinct transcriptional, phenotypic, and metabolic signatures eng 2022-02-23 2022-02-23 author Dubouchet Laetitia 0000-0002-8009-5171 672274 author Todorov Helena 0000-0002-1594-8609 931538 author Seurinck Ruth author Vallet Nicolas author Van Gassen Sofie author Corneau Aurélien author Blanc Catherine author Zouali Habib author Boland Anne author Deleuze Jean-François author Ingram Brian author de Latour Regis Peffault author Saeys Yvan author Socié Gérard author Michonneau David eabg3083 10.1126/scitranslmed.abg3083 35196024 1946-6234 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<sup>+</sup>-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 <i>NT5E</i>(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. HLA Antigens Hematopoietic Stem Cell Transplantation* Humans Immune Tolerance* Transplantation Tolerance / genetics true 1216 Leucémie et transplantation allogénique de cellules souches hématopoïétiques 982 Science translational medicine 14 633 f7bce77a-49ef-401b-9209-dd9073164f97 Article (Published version) Public article_publication_Science Transla.pdf 906624 application/pdf openAccess

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Operational tolerance after hematopoietic stem cell transplantation is characterized by distinct transcriptional, phenotypic, and metabolic signatures	Science translational medicine			2022	287	744

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Todorov, Helena