γδT cell-mediated regulation of chemokine producing macrophages during Listeria monocytogenes infection-induced inflammation

Infection of gamma delta T cell-deficient (TcR delta(-/-)) mice with the intracellular bacterium Listeria monocytogenes (Lm) results in an exacerbated inflammatory response characterized by the accumulation of activated macrophages and necrotic liver lesions. Here we investigated whether changes in chemokine production by Lm-elicited macrophages contribute to this abnormal inflammatory response. In response to Lm infection, activated macrophages accumulate in the primary sites of infection in TcR delta(-/-) mice and express high amounts of mRNA encoding the chemokines CCL3 (MIP-1 alpha), CCL4 (MIP-1 beta), CXCL2 (MIP-2) and CXCL10 (IP-10). In the infected tissues of TcR delta(-/-) the number of chemokine-synthesizing macrophages was higher than in wild-type (WT) mice, with the amount of MIP-1 alpha and MIP-1 beta secreted by individual macrophages in the spleen of TcR delta(-/-) mice also being significantly higher than in WT mice. By contrast, protease activity and NO production in individual splenic macrophages of Lm-infected TcR delta(-/-) and WT mice were comparable. Pathogen-elicited macrophages in TcR delta(-/-) mice also expressed high levels of the CCL3 and CCL4 receptor, CCR5. In macrophage-gamma delta T cell co-cultures, chemokine-producing macrophages were killed by cytotoxic V gamma 1(+) T cells in a Fas-FasL-dependent manner consistent with the high levels of chemokine-producing macrophages seen in infected TcR delta(-/-) mice being due to the absence of V gamma 1(+) T cells. Together these findings highlight the importance of gamma delta T cells in regulating macrophage anti-microbial responses. Copyright (C) 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.