Leukotriene B4 regulates T cell recognition and control of MCMV in mucosal tissues.

Abstract

Lipid mediators play important, yet poorly understood roles in regulating immune responses. Cytomegalovirus (CMV) is a herpesvirus that persists in mucosal tissues. Prior work suggests that leukotrienes, a class of inflammatory lipid mediators, contribute to viral control. Infection with murine (M)CMV altered leukotriene and other lipid mediator production in the nasal mucosa, lungs and salivary glands of mice. Mice lacking the receptor for leukotriene B4 (BLT1^-/-) had increased viral titers at early timepoints in the nasal mucosa and lungs and produced less interferon (IFN)-γ in both tissues, altering the balance between IFN-γ and interleukin (IL)-10. Importantly, viral control in BLT1^-/- mice was restored by IL-10 blockade, showing that leukotriene B4 promotes an optimal IFN-γ/IL-10 balance in these mucosal sites during acute infection. BLT1^-/- T cells showed no defects in the ability to produce IFN-γ, but their gene expression profiles suggested reduced activation and altered migratory capacity. MCMV-specific T cells compete for access to infected cells. Remarkably, when in competition with wild-type T cells, BLT1^-/- T cells competed poorly for antigen, resulting in reduced expansion. These data suggest that leukotriene B4 promotes control of CMV by optimizing T cell encounters with infected targets, maintaining the balance between IFN-γ and IL-10.