A subset of IL-10-producing γδ T cells protect the liver from Listeria-elicited, CD8+ T cell-mediated injury

Although γδ T cells play a role in protecting tissues from pathogen-elicited damage to bacterial, viral and parasitic pathogens, the mechanisms involved in the damage and in the protection have not been clearly elucidated. This has been addressed using a murine model of listeriosis, which in mice lacking γδ T cells (TCRδ -/-) is characterised by severe and extensive immune-mediated hepatic necrosis. We show that these hepatic lesions are caused by Listeria-elicited CD8+ T cells secreting high levels of TNF-α that accumulate in the liver of Listeria-infected TCRδ-/- mice. Using isolated populations of γδ T cells from wild-type and cytokine-deficient strains of mice to reconstitute TCRδ -/- mice, the TCR variable gene 4 (Vγ4)+ subset of γδ T cells was shown to protect against liver injury. Hepatoprotection was dependent upon their ability to produce IL-10 after TCR-mediated interactions with Listeria-elicited macrophages and CD8+ T cells. IL-10-producing Vγ4+ T cells also contribute to controlling CD8+ T cell expansion and to regulating and reducing TNF-α secretion by activated CD8+ T cells. This effect on TNF-α production was directly attributed to IL-10. These findings identify a novel mechanism by which pathogen-elicited CD8+ T cells are regulated via interactions with, and activation of, IL-10-producing hepatoprotective γδ T cells. © 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.