IL-34 is a Treg-specific cytokine and mediates transplant tolerance
Séverine Bézie, Elodie Picarda, Jason Ossart, Laurent Tesson, Claire Usal, Karine Renaudin, Ignacio Anegon, Carole Guillonneau
Séverine Bézie, Elodie Picarda, Jason Ossart, Laurent Tesson, Claire Usal, Karine Renaudin, Ignacio Anegon, Carole Guillonneau
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Research Article

IL-34 is a Treg-specific cytokine and mediates transplant tolerance

Abstract

Cytokines and metabolic pathway–controlling enzymes regulate immune responses and have potential as powerful tools to mediate immune tolerance. Blockade of the interaction between CD40 and CD40L induces long-term cardiac allograft survival in rats through a CD8+CD45RClo Treg potentiation. Here, we have shown that the cytokine IL-34, the immunoregulatory properties of which have not been previously studied in transplantation or T cell biology, is expressed by rodent CD8+CD45RClo Tregs and human FOXP3+CD45RCloCD8+ and CD4+ Tregs. IL-34 was involved in the suppressive function of both CD8+ and CD4+ Tregs and markedly inhibited alloreactive immune responses. Additionally, in a rat cardiac allograft model, IL-34 potently induced transplant tolerance that was associated with a total inhibition of alloantibody production. Treatment of rats with IL-34 promoted allograft tolerance that was mediated by induction of CD8+ and CD4+ Tregs. Moreover, these Tregs were capable of serial tolerance induction through modulation of macrophages that migrate early to the graft. Finally, we demonstrated that human macrophages cultured in the presence of IL-34 greatly expanded CD8+ and CD4+ FOXP3+ Tregs, with a superior suppressive potential of antidonor immune responses compared with non–IL-34–expanded Tregs. In conclusion, we reveal that IL-34 serves as a suppressive Treg–specific cytokine and as a tolerogenic cytokine that efficiently inhibits alloreactive immune responses and mediates transplant tolerance.

Authors

Séverine Bézie, Elodie Picarda, Jason Ossart, Laurent Tesson, Claire Usal, Karine Renaudin, Ignacio Anegon, Carole Guillonneau

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Figure 2

IL-34 is a human FOXP3+ Treg–specific cytokine involved in the suppressive activity of antidonor immune responses.

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IL-34 is a human FOXP3+ Treg–specific cytokine involved in the suppressi...
The percentage of IL-34+ cells in healthy individuals was evaluated in CD4+ or CD8+ CD45RClo or CD45RChi T cells (A) or in FOXP3+ versus FOXP3– CD45RClo CD8+ or CD4+ T cells (B and C). (A) The mean ± SEM of 27 healthy individuals is represented. Mann-Whitney U test, *P < 0.05, ***P < 0.001. Representative histogram and plot of healthy individuals (B) showing the mean of expression ± SEM of 10 healthy individuals (C). (D) Soluble IL-34 was tested for suppression of CD4+CD25– T cell proliferation in response to allogeneic T cell–depleted PBMCs and analyzed by flow cytometry for CFSE dilution after 5 days of culture (n = 2–5 experiments performed in duplicate). Results are expressed as the mean ± SEM of the relative proportion of dividing CD4+CD25– T cells. Representative histogram of 1 experiment: Proliferation of CFSE-labeled CD4+CD25– T cells cocultured with T cell–depleted PBMCs with increased concentrations of IL-34. Two-way ANOVA with Bonferroni’s post test versus M-CSF, ***P < 0.001. (E) The relative proportion of CFSE-labeled dividing CD4+CD25– T cells stimulated with allogeneic T cell–depleted PBMCs was analyzed after 5 days of culture, in the presence of CD8+CD45RClo or CD4+CD25hiCD127– Tregs at 1:1 effector/suppressor ratios. The proliferation after addition of anti–IL-34–blocking Ab was evaluated and compared with isotypic control (n = 5–6 experiments performed in triplicate). The proportion of dividing CD4+CD25– T cells in the control proliferation condition with allogeneic T cell–depleted PBMCs only represented approximately 60% of the cells on day 5 and was given a value of 100 in each experiment. Results are expressed as the mean ± SEM of the relative proportion of dividing CD4+CD25– T cells. A representative raw CFSE profile is shown in the right panel. Wilcoxon test (versus proliferation without Tregs = 100), **P < 0.01.