Loss of L-selectin-guided CD8⁺ , but not CD4⁺ , cells protects against ischemia reperfusion injury in a steatotic liver.

Steatotic liver responds with increased hepatocellular injury when exposed to an ischemic-reperfusion insult. Increasing evidence supports the role of immune cells as key mediators of this injury in a normal (lean) state, but data about their role in a steatotic liver are practically nonexistent. The objective of the current study was to delineate the contribution of specific phenotypes of T cells and adhesion molecules in exacerbated cell death in steatotic liver injury. RNA sequencing was performed on isolated steatotic primary hepatocytes, and T-cell markers were assessed in hepatic lymphocytes after ischemia reperfusion injury (IRI) in high-fat diet (HFD)-fed mice. Cluster of differentiation 8 knockout (CD8^-/- ) and CD4^-/- mice along with CD8 and L-selectin antibody-treated mice were fed an HFD, and hepatocellular injury was assessed by histology, propidium iodide injection, and alanine aminotransferase after IRI. RNA sequencing demonstrated a strikingly differential gene profile in steatotic hepatocytes versus lean hepatocytes. After injury, the HFD liver showed increased necrosis, infiltrating CD8⁺ cells, alanine aminotransferase, and proinflammatory cytokines. Hepatic lymphocytes demonstrated increased CD8⁺ /CD62L⁺ (L-selectin) cells in HFD-fed mice after IRI. CD8^-/- mice and CD8-depleted C57BL/6 mice demonstrated significant protection from injury, which was not seen in CD4^-/- mice. L-selectin blockade also demonstrated significant hepatoprotection from IRI. L-selectin ligand MECA-79 was increased in HFD-fed mice undergoing IRI. CONCLUSION:Blockade of CD8 and L-selectin, but not CD4, ameliorated hepatocellular injury, confirming that CD8⁺ cells are critical drivers of injury in a steatotic liver; this represents a therapeutic target in steatotic liver injury, underlining the importance of development of therapies specific to a steatotic liver. (Hepatology 2017;66:1258-1274).

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