Immunoregulatory function of IL-27 and TGF-β1 in cardiac allograft transplantation

L Le Texier, P Thebault, M Carvalho-Gaspar… - …, 2012 - journals.lww.com
L Le Texier, P Thebault, M Carvalho-Gaspar, V Vignard, E Merieau, C Usal, MC Cuturi…
Transplantation, 2012journals.lww.com
Background Deciphering the mechanisms of tolerance represents a crucial aim of research
in transplantation. We previously identified by DNA chip interleukin (IL)-27 p28 and
transforming growth factor (TGF)–β1 as overexpressed in a model of rat cardiac allograft
tolerance mediated by regulatory CD4+ CD25+ T cells. The role of these two molecules on
the control of the inflammatory response remains controversial. However, both are involved
in the regulation of the T helper 17/Treg axis, suggesting their involvement in tolerance …
Abstract
Background
Deciphering the mechanisms of tolerance represents a crucial aim of research in transplantation. We previously identified by DNA chip interleukin (IL)-27 p28 and transforming growth factor (TGF)–β1 as overexpressed in a model of rat cardiac allograft tolerance mediated by regulatory CD4+ CD25+ T cells. The role of these two molecules on the control of the inflammatory response remains controversial. However, both are involved in the regulation of the T helper 17/Treg axis, suggesting their involvement in tolerance.
Methods
We analyzed regulation of IL-27 and TGF-β1 expression in allograft response and their role in tolerance by using blocking anti–TGF-β antibody and by generating an adeno-associated virus encoding IL-27.
Results
Here, we confirmed the overexpression of IL-27 and TGF-β1 in tolerated cardiac allografts in two different rodent models. We observed that their expression correlates with inhibition of T helper 17 differentiation and with expansion of regulatory CD4+ CD25+ T cells. We showed in a rat model that anti–TGF-β treatment abrogates infectious tolerance mediated by the transfer of regulatory CD4+ CD25+ T cells. Moreover, overexpression of IL-27 by adeno-associated virus administration in combination with a short-term immunosuppression allows prolongation of cardiac allograft survival and one tolerant recipient. We found that IL-27 overexpression did not induce Foxp3+ CD4+ CD25+ T-cell expansion but rather IL-10–expressing CD4+ T cells in the tolerant recipient.
Conclusions
Taken together, these data suggest that both TGF-β1 and IL-27 play a role in the mechanisms of tolerance. However, in contrast to TGF-β1, IL-27 seems not to be involved in regulatory CD4+ CD25+ T-cell expansion but rather in their mode of action.
Lippincott Williams & Wilkins