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

Although gamma delta 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 gamma delta T cells (TCR6-1-) 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-alpha that accumulate in the liver of Listeria-infected TCR delta(-/-) mice. Using isolated populations of gamma delta T cells from wild-type and cytokine-deficient strains of mice to reconstitute TCR delta(-/-) mice, the TCR variable gene 4 (V gamma 4)(+) subset of gamma delta T cells was shown to protect against liver injury. Hepatoprotection was dependent upon their ability to produce IL-10 after TCR-mediated interactions with Listeriaelicited macrophages and CD8(+) T cells. IL-10-producing V gamma 4' T cells also contribute to controlling CD8(+) T cell expansion and to regulating and reducing TNF-a secretion by activated CD8(+) T cells. This effect on TNF-ct 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 gamma delta T cells.