Ischemia reperfusion injury (IRI) remains an important problem in organ transplantation. Growing evidence suggests that CD3+ T cells play a key role in early hepatic IRI, however, the type of T cells involved and the underlying mechanisms remain poorly understood. Here, we investigated early immunological events in a well-established model of hepatic IRI in genetically targeted mice to study the pathomechanistic role of RORΓt+ T cells. We used heterozygous B6.RORΓt-gfp/wt-reporter and homozygous B6.RORΓt-gfp/gfp-knockout (ko) mice that underwent a 90 min partial warm ischemia, followed by 24 hours of reperfusion. Hepatocellular injury was evaluated by HE-histology and serum-transaminase (ALT, AST) measurements. Hepatic leukocyte subsets, cytokine secretion and major effector molecules were characterized by immunohistochemistry, ELISA, RT-PCR and polychromatic FACS. With this method we found unconventional CD27-ΓΔTCR+ and CD4-CD8- double-negative (DN) T cells being the primary IL-17A expressing cells in hepatic IRI. Mice deficient for ΓΔTCR+ T cells were protected from hepatic IRI, but liver damage was restored after adoptive transfer of ΓΔTCR+ T cells from wt animals. We further show that unconventional IRI-mediating T cells are dependent on RORΓt, as highlighted by the fact that a genetic deficiency for RORΓt, or its therapeutic antagonization via digoxin, protected against hepatic IRI. Therefore, identification of CD27-ΓΔTCR+ and CD4-CD8- DN T cells as the major source of IL-17A via RORΓt in hepatic IRI opens new therapeutic options to improve liver transplant outcomes.
To cite this abstract in AMA style:Eggenhofer E, Groell A, Scherer M, Farkas S, Loss M, Rovira J, Sabet-Baktach M, Koehl G, Melter M, Schlitt H, Geissler E, Kroemer A. Unconventional RORγt+ T Cells Drive Hepatic Ischemia Reperfusion Injury [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/unconventional-rort-t-cells-drive-hepatic-ischemia-reperfusion-injury/. Accessed October 31, 2020.
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