Evaluation of immune T-cells responsible for tissue repair in human liver transplantation and in a mouse model of hepatic ischemia reperfusion
BOST R. 1,2, ROBIN A. 1,2,3, MACKOWIAK C. 1,2, PELLERIN L. 1,2,3, SALAMÉ E. 4,5, GOMBERT J. 1,2,3, BARBIER L. 4,5, HERBELIN A. 1,2
1 INSERM U1313, FHU SUPORT, Poitiers, France, Poitiers, France; 2 University of Poitiers, Poitiers, France, Poitiers, France; 3 University hospital of Poitiers, France, Poitiers, France; 4 Digestive surgery and liver transplantation, university hospital of Tours, France, Tours, France; 5 University of Tours, Tours, France, Tours, France
We recently demonstrated the involvement of the IL-33 alarmin/innate T-cell (ITC) axis during acute sterile inflammation in response to hepatic ischemia-reperfusion (IR). Immune system plays a crucial role in repair and returning to homeostatic conditions after acute inflammation. Here, we analyzed the influence of human liver transplantation (LT) and hepatic IR in mice on the relative proportion and activation of ITCs (iNKT, MAIT, T-gd cells) and regulatory T CD4 lymphocytes (Treg), which express IL-33 receptor and are known to repair/regulate inflammation.
A biological collection of LT recipients was established at the University Hospital Center of Tours. Peripheral mononuclear cells were isolated from blood collected before (D0) and at the end of LT (EoT), one (D1) and seven days (D7) after LT. A hepatic IR model was performed in wild-type (WT) and IL-33-deficient (IL-33KO) mice. Liver mouse samples were collected, and immune cells were isolated at D3, D7 and D15 after IR. All the samples were analyzed by spectral flow cytometry.
In both LT and mouse IR model, proportion and activation level of Treg increased at D7 compared to D0. Importantly, in LT, increase of Treg correlated with IL-33 release at EoT, while in the mouse IR model, it disappeared when IL-33KO mice were used instead of WT mice, confirming the role of IL-33 in this phenomenon. Considering ITCs, early activation of MAIT, iNKT and gd-T cells, which was observed at EoT, was maintained until D7. In mice, activation of ITCs was accompanied by intra-hepatic accumulation of iNKT, MAIT and gd-T cells between D3 and D15 post-liver IR.
Our data suggest a contribution of IL-33 with both Treg and ITCs in repair/resolution of sterile inflammation in response to IR. Further studies are needed to directly identify the underlying molecular repair functions put in play by Treg and ITCs.