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 8

Regulatory potential and host reactivity of donor-derived DP8α Tregs tend to discriminate patients who will develop aGvHD from those who will not.

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Regulatory potential and host reactivity of donor-derived DP8α Tregs ten...
(A and B) Circulating DP8α Treg frequency among indicated T cell subsets (A) and their CD73 expression (B) are shown for allograft donors before inducing mobilization with granulocyte colony–stimulating factor (G-CSF). (C and D) Circulating DP8α Treg frequency among indicated T cell subsets (C) and their CD73 expression (D) are shown on mobilized blood donors and thus corresponds to the actual grafted cells. (E) CD73+ DP8α Treg frequencies in bone marrow samples before transplantation. (F and G) CD4+ T cells, comprising DP8α Tregs, derived from HSCs’ donors were magnetically sorted and stained with 1 mM VPD before being cocultured in the presence of low-dose IL-2 (20 IU/mL) with either patient-derived magnetically sorted monocytes (ratio 1:1) (obtained before transplantation) previously loaded overnight or not with F. prausnitzii (ratio 1 monocyte:5 bacteria) or with magnetically sorted monocytes from the corresponding donors (ratio 1:1). Five days later, T cell proliferation of gated DP8α cells was measured through VDP dilution assessment by flow cytometry. Patients developing aGvHD or not (G; red and green, respectively) are shown. Results are represented as mean ± SEM. SP, single-positive. (H and I) Cumulative aGvHD incidence was plotted for low versus high allogeneic host-reactive DP8α cells (H) or F. prausnitzii–reactive DP8α cells (I), in all patients. Cutoff was determined using the median of host-reactive cells (= 9.5%, H) or F. prausnitzii–reactive cells (= 14.8%, I) among total DP8α cells. Log-rank (Mantel-Cox) test was used.