Immunoregulatory function of IL-27 and TGF-β1 in cardiac allograft transplantation.
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 CD4CD25 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 CD4CD25 T cells. We showed in a rat model that anti-TGF-β treatment abrogates infectious tolerance mediated by the transfer of regulatory CD4CD25 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 Foxp3CD4CD25 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 CD4CD25 T-cell expansion but rather in their mode of action.
Institut National de la Santé Et de la Recherche Médicale U1064, Nantes, France.
Laetitia
L
Le Texier
Pamela
P
Thebault
Manuela
M
Carvalho-Gaspar
Virginie
V
Vignard
Emmanuel
E
Merieau
Claire
C
Usal
Maria-Cristina
MC
Cuturi
Kathryn J
KJ
Wood
Elise
E
Chiffoleau
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D002454:Cell Differentiation; D000229:Dependovirus / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D016027:Heart Transplantation / Q000379:methods*; D007249:Inflammation; D020381:Interleukin-17 / Q000378:metabolism*; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D058504:Th17 Cells / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D014184:Transplantation, Homologous
D020381:Interleukin-17; D053645:Interleukin-2 Receptor alpha Subunit; D053773:Transforming Growth Factor beta1