Unconventional RORγt+ T Cells Drive Hepatic Ischemia Reperfusion Injury

An emerging body of evidence suggests a pivotal role of CD3(+) T cells in mediating early ischemia reperfusion injury (IRI). However, the precise phenotype of T cells involved and the mechanisms underlying such T cell-mediated immune responses in IRI, as well as their clinical relevance, are poorly understood. In this study, we investigated early immunological events in a model of partial warm hepatic IRI in genetically targeted mice to study the precise pathomechanistic role of ROR gamma t(+) T cells. We found that unconventional CD27(-)gamma delta TCR+ and CD4(-)CD8(-) double-negative T cells are the major ROR gamma t-expressing effector cells in hepatic IRI that play a mechanistic role by being the main source of IRI-mediating IL-17A. We further show that unconventional IRI-mediating T cells are contingent on ROR gamma t, as highlighted by the fact that a genetic deficiency for RORgt, or its therapeutic antagonization via digoxin, is protective against hepatic IRI. Therefore, identification of CD27(-)gamma delta TCR+ and CD4(-)CD8(-) double-negative T cells as the major source of IL-17A via ROR gamma t in hepatic IRI opens new therapeutic options to improve liver transplantation outcomes.