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 7

CD73 drives DP8α Treg suppressive activity.

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CD73 drives DP8α Treg suppressive activity. (A and B) Eight different DP...
(A and B) Eight different DP8α Treg clones, whose CD73 expression is shown for a representative clone (Figure 2A), were all separately cocultured with sorted and VPD-stained CD4+ T cells derived from 4 different healthy donors (1:1 ratio) in the presence or absence of CD73 inhibitors (adenosine 5′-[α,β-methylene]diphosphate sodium salt at 2 mM, 20 mM, and 200 mM; PBS 12379 at 10 nM, 100 nM, and 1 mM; AB-680 at 5 nM, 50 nM, and 500 nM; blocking anti-CD73 antibody at 2 mM, 5 mM, and 20 mM). Proliferation was measured 5–6 days later as the percentage of VPDlo CD4+ T cells. (A) A representative example for the coculture of a DP8α Treg clone with CD4+ T cells from 1 donor, with or without the CD73 inhibitor AB-680 at indicated concentrations, is shown. (B) The entire data set from this experiment is presented. One-way ANOVA with post hoc Dunnett’s multiple-comparison test was used to compare indicated conditions to the “no-treatment” data, corresponding to DP8α Treg inhibition of CD4+ T cell proliferation in the absence of any inhibitor. Results are represented as mean ± SEM.