Human gut microbiota–reactive DP8α Tregs prevent acute graft-versus-host disease in a CD73-dependent manner
Emmanuelle Godefroy, Patrice Chevallier, Fabienne Haspot, Caroline Vignes, Véronique Daguin, Sylvia Lambot, Margaux Verdon, Margaux De Seilhac, Valentin Letailleur, Anne Jarry, Annabelle Pédron, Thierry Guillaume, Pierre Peterlin, Alice Garnier, Marie-Anne Vibet, Maxence Mougon, Amandine Le Bourgeois, Maxime Jullien, Francine Jotereau, Frédéric Altare
Emmanuelle Godefroy, Patrice Chevallier, Fabienne Haspot, Caroline Vignes, Véronique Daguin, Sylvia Lambot, Margaux Verdon, Margaux De Seilhac, Valentin Letailleur, Anne Jarry, Annabelle Pédron, Thierry Guillaume, Pierre Peterlin, Alice Garnier, Marie-Anne Vibet, Maxence Mougon, Amandine Le Bourgeois, Maxime Jullien, Francine Jotereau, Frédéric Altare
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Research Article Immunology Transplantation

Human gut microbiota–reactive DP8α Tregs prevent acute graft-versus-host disease in a CD73-dependent manner

Abstract

Graft-versus-host disease (GvHD) is a life-threatening complication frequently occurring following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Since gut microbiota and regulatory T cells (Tregs) are believed to play roles in GvHD prevention, we investigated whether DP8α Tregs, which we have previously described to harbor a T cell receptor specificity for the gut commensal Faecalibacterium prausnitzii, could protect against GvHD, thereby linking the microbiota and its effect on GvHD. We observed a decrease in CD73+ DP8α Treg frequency in allo-HSCT patients 1 month after transplantation, which was associated with acute GvHD (aGvHD) development at 1 month after transplantation, as compared with aGvHD-free patients, without being correlated to hematological disease relapse. Importantly, CD73 activity was shown to be critical for DP8α Treg suppressive function. Moreover, the frequency of host-reactive DP8α Tregs was also lower in aGvHD patients, as compared with aGvHD-free patients, which could embody a protective mechanism responsible for the maintenance of this cell subset in GvHD-free patients. We also showed that human DP8α Tregs protected mice against xenogeneic GvHD through limiting deleterious inflammation and preserving gut integrity. Altogether, these results demonstrated that human DP8α Tregs mediate aGvHD prevention in a CD73-dependent manner, likely through host reactivity, advocating for the use of these cells for the development of innovative therapeutic strategies to preclude aGvHD-related inflammation.

Authors

Emmanuelle Godefroy, Patrice Chevallier, Fabienne Haspot, Caroline Vignes, Véronique Daguin, Sylvia Lambot, Margaux Verdon, Margaux De Seilhac, Valentin Letailleur, Anne Jarry, Annabelle Pédron, Thierry Guillaume, Pierre Peterlin, Alice Garnier, Marie-Anne Vibet, Maxence Mougon, Amandine Le Bourgeois, Maxime Jullien, Francine Jotereau, Frédéric Altare

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Figure 1

CD73 expression and, to a lower extent, DP8α Treg frequency, is specifically decreased in aGvHD patients 1 month after transplantation.

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CD73 expression and, to a lower extent, DP8α Treg frequency, is specific...
(A) The gating strategy to study DP8α Tregs is shown. (B and G) Blood samples from healthy donors (HD) and from patients with hematological malignancies were collected before receiving allo-HSCT (pre-Tx, d–7) and at 1 month after transplantation (post-Tx). Samples were analyzed by flow cytometry to assess CD3+, CD4+, CD8αlo, CCR6+, and CXCR6+ DP8α Treg–related characteristics, including their CD73 expression pattern shown here at indicated time points. All patients tested (B) and representative examples at d30 (C) are shown. One-way ANOVA (Kruskal-Wallis test) followed by Dunn’s multiple-comparison test to obtain adjusted P values was used. (D) DP8α Treg frequency among total CD3+ T cells is shown at indicated time points. (E) CD39 expression on DP8α Tregs from allo-HSCT patients is shown at indicated time points. (F) CD73 expression, on d30 after transplantation, by indicated T cell subset: total single-positive (SP) CD4+ T cells, total SP CD8+ T cells, and DP8α non-Treg cells, annotated DP8α CCR-neg (i.e., DP8α cells comprising CCR6–CXCR6–, CCR6+CXCR6–, and CCR6–CXCR6+ fractions) is shown. Mann-Whitney tests were performed for single comparisons. (G) Cell frequencies of indicated subsets on d30 after transplantation in aGvHD patients are shown. Mann-Whitney tests were performed for single comparisons.