No abstract

γδ T cells play important but poorly defined roles in pathogen-induced immune responses and in preventing chronic inflammation and pathology. A major obstacle to defining their function is establishing the degree of functional redundancy and heterogeneity among γδ T cells. Using mice deficient in Vγ1+ T cells which are a major component of the γδ T cell response to microbial infection, a specific immunoregulatory role for Vγ1+ T cells in macrophage and γδ T cell homeostasis during infection has been established. By contrast, Vγ1+ T cells play no significant role in pathogen containment or eradication and cannot protect mice from immune-mediated pathology. Pathogen-elicited Vγ1+ T cells also display different functional characteristics at different stages of the host response to infection that involves unique and different populations of Vγ1+ T cells. These findings, therefore, identify distinct and nonoverlapping roles for γδ T cell subsets in infection and establish the complexity and adaptability of a single population of γδ T cells in the host response to infection that is not predetermined, but is, instead, shaped by environmental factors.

Although cd 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 cd T cells (TCRd -/-) 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-a that accumulate in the liver of Listeria-infected TCRd -/-mice. Using isolated populations of cd T cells from wild-type and cytokine-deficient strains of mice to reconstitute TCRd -/-mice, the TCR variable gene 4 (Vc4) + subset of cd 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 Vc4 + 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-a 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 cd T cells.