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
View: Text | PDF
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

×

Figure 2

CD73+ DP8α Treg abundance is associated with aGvHD occurrence and severity, but not with cGvHD.

Options: View larger image (or click on image) Download as PowerPoint
CD73+ DP8α Treg abundance is associated with aGvHD occurrence and severi...
(A) CD73+ DP8α Treg frequencies are shown in HD and allo-HSCT patients, both before and after transplantation in aGvHD and aGvHD-free patients. One-way ANOVA (Kruskal-Wallis tests) followed by Dunn’s multiple-comparison test to obtain adjusted P values was used. Results are represented as mean ± SEM. (B) Cumulative aGvHD incidence over time was plotted for low versus high CD73+ DP8α Treg abundance. Cutoff was determined using the median of CD73+ DP8α Treg frequency among total T cells (= 0.0050%) from all patients. The Fine-Gray method, with relapse or death as competing risks, was used (shaded area: 95% CI). (C) Cumulative aGvHD incidence over time was plotted for low versus high CD73+ DP8α Treg abundance in the aGvHD-positive subgroup, using the median of this group of patients (= 0.00115%) as a cutoff. Log-rank (Mantel-Cox) test was used; shaded area is 95% CI. (D) Absolute numbers of CD73+ DP8α Tregs in 30 mL samples in aGvHD versus aGvHD-free patients were calculated using CBC clinical data. Mann-Whitney test was used to compare both groups (mean ± SEM). (E) CD73+ DP8α Treg frequencies are shown in HD and allo-HSCT patients, in cGvHD and cGvHD-free patients (1-way ANOVA [Kruskal-Wallis test] followed by Dunn’s multiple-comparison test, mean ± SEM). (F) Cumulative cGvHD incidence, over approximatively 1500 days (corresponding to the 52-week median follow-up for this cohort, calculated using reverse Kaplan-Meier), was plotted for low versus high CD73+ DP8α Treg abundance in all patients (same cutoff as above, Fine-Gray test with relapse or death as competing risks; shaded area is 95% CI). (G) Cumulative cGvHD incidence was plotted for low versus high CD73+ DP8α Treg abundance in the cGvHD-positive subgroup, using the median of this group of patients (= 0.0045%) as a cutoff (Fine-Gray test with relapse or death as competing risks; shaded area is 95% CI). (H) CD73+ DP8α Treg frequencies are shown in indicated patients’ groups (1-way ANOVA). (I) Absolute numbers of CD73+ DP8α Tregs in 30 mL samples in cGvHD versus aGvHD-free patients. Mann-Whitney test was used to compare both groups (mean ± SEM). (J) CD73+ DP8α Treg frequencies are shown in HD and allo-HSCT patients, in patients who died of GvHD or not (1-way ANOVA [Kruskal-Wallis test] followed by Dunn’s multiple-comparison test, mean ± SEM). (K) Cumulative death by aGvHD incidence was plotted for low versus high CD73+ DP8α Treg abundance in all patients (same cutoff as above, Fine-Gray test with death unrelated to aGVHD as a competing risk). (L) Absolute numbers of CD73+ DP8α Tregs in 30 mL samples in patients who died of aGvHD or not. Mann-Whitney test was used to compare both groups (mean ± SEM).