gammadeltaT cell-mediated regulation of chemokine producing macrophages during Listeria monocytogenes infection-induced inflammation.
Infection of gammadeltaT cell-deficient (TcRdelta-/-) 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 TcRdelta-/- mice and express high amounts of mRNA encoding the chemokines CCL3 (MIP-1alpha), CCL4 (MIP-1beta), CXCL2 (MIP-2) and CXCL10 (IP-10). In the infected tissues of TcRdelta-/- the number of chemokine-synthesizing macrophages was higher than in wild-type (WT) mice, with the amount of MIP-1alpha and MIP-1beta secreted by individual macrophages in the spleen of TcRdelta-/- mice also being significantly higher than in WT mice. By contrast, protease activity and NO production in individual splenic macrophages of Lm-infected TcRdelta-/- and WT mice were comparable. Pathogen-elicited macrophages in TcRdelta-/- mice also expressed high levels of the CCL3 and CCL4 receptor, CCR5. In macrophage-gammadeltaT cell co-cultures, chemokine-producing macrophages were killed by cytotoxic Vgamma1+ T cells in a Fas-FasL-dependent manner consistent with the high levels of chemokine-producing macrophages seen in infected TcRdelta-/- mice being due to the absence of Vgamma1+ T cells. Together these findings highlight the importance of gammadeltaT cells in regulating macrophage anti-microbial responses.
Tramonti
D
D
Research Institute of Molecular and Cellular Biology, University of Leeds, Leeds LS29JT, UK.
Rhodes
K
K
Martin
N
N
Dalton
J E
JE
Andrew
E
E
Carding
S R
SR