1. Unconventional RORγt+ T Cells Drive Hepatic Ischemia Reperfusion Injury
- Author
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M. Sabet-Baktach, Marc-Hendrik Dahlke, Alexander Kroemer, Anja Groell, Jordi Rovira, Michael Melter, Hans J. Schlitt, Edward K. Geissler, Elke Eggenhofer, Martin Loss, Sven A. Lang, Stefan Farkas, Gudrun E. Koehl, and Marcus N. Scherer
- Subjects
Time Factors ,CD3 ,medicine.medical_treatment ,Immunology ,Ischemia ,Hepatitis, Animal ,Liver transplantation ,urologic and male genital diseases ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Genes, Reporter ,T-Lymphocyte Subsets ,RAR-related orphan receptor gamma ,Animals ,Immunology and Allergy ,Medicine ,cardiovascular diseases ,030304 developmental biology ,Mice, Knockout ,0303 health sciences ,biology ,urogenital system ,business.industry ,Effector ,fungi ,Nuclear Receptor Subfamily 1, Group F, Member 3 ,medicine.disease ,Phenotype ,female genital diseases and pregnancy complications ,3. Good health ,Mice, Inbred C57BL ,Disease Models, Animal ,Reperfusion Injury ,biology.protein ,030211 gastroenterology & hepatology ,business ,Reperfusion injury - Abstract
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 RORγt+ T cells. We found that unconventional CD27−γδTCR+ and CD4−CD8− double-negative T cells are the major RORγt-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 RORγt, as highlighted by the fact that a genetic deficiency for RORγt, or its therapeutic antagonization via digoxin, is protective against hepatic IRI. Therefore, identification of CD27−γδTCR+ and CD4−CD8− double-negative T cells as the major source of IL-17A via RORγt in hepatic IRI opens new therapeutic options to improve liver transplantation outcomes.
- Published
- 2013