Innate Activation of IFN-γ—iNOS Axis During Infection With Salmonella Represses the Ability of T Cells to Produce IL-2

Abstract

Pathogenic <i>Salmonella</i> serovars are a major cause of enteric illness in humans and animals, and produce clinical manifestations ranging from localized gastroenteritis to systemic disease. T cells are a critical component of immunity against this intracellular pathogen. The mechanisms by which <i>Salmonella</i> modulates T-cell-mediated immune responses in order to establish systemic infection are not completely understood. We show that infection of mice with <i>Salmonella enterica</i> serovar Typhimurium (<i>S</i>. Typhimurium) suppresses IL-2 and increases IFN-γ and IL-17 production from T cells activated <i>in vivo</i> or <i>ex vivo</i> through the T cell receptor. Infection with <i>S</i>. Typhimurium brings about recruitment of CD11b⁺Gr1⁺ suppressor cells to the spleen. <i>Ex vivo</i> depletion of these cells restores the ability of activated T cells to produce IL-2 and brings secretion of IFN-γ and IL-17 from these cells back to basal levels. The reduction in IL-2 secretion is not seen in IFN-γ^-/- and iNOS^-/- mice infected with <i>Salmonella</i>. Our findings demonstrate that sustained innate activated IFN-γ production during progression of infection with <i>Salmonella</i> reduces IL-2-secreting capability of T cells through an iNOS-mediated signaling pathway that can adversely affect long term immunity against this pathogen.