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

Abstract

Pathogenic Salmonella 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 Salmonella modulates T-cell-mediated immune responses in order to establish systemic infection are not completely understood. We show that infection of mice with Salmonella enterica serovar Typhimurium (S. Typhimurium) suppresses IL-2 and increases IFN-γ and IL-17 production from T cells activated in vivo or ex vivo through the T cell receptor. Infection with S. Typhimurium brings about recruitment of CD11b + Gr1 + suppressor cells to the spleen. Ex vivo 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 Salmonella. Our findings demonstrate that sustained innate activated IFN-γ production during progression of infection with Salmonella reduces IL-2-secreting capability of T cells through an iNOS-mediated signaling pathway that can adversely affect long term immunity against this pathogen.

Early induction of antibacterial activities distinguishes response of mice to infection with non-permissive from response to permissiveSalmonella

“…Similar changes in cellularity have been previously reported in the peritoneal cavities and spleens of mice infected with pathogenic Salmonella and these have been associated with immunomodulatory roles in the establishment of infection with this pathogen [14][15][16].…”

GH18 family glycoside hydrolase Chitinase A of Salmonella enhances virulence by facilitating invasion and modulating host immune responses

“…In vivo infection in C57BL/6 mice suggested that STM Δ chiA mutant could not invade the PP, leading to an early fecal shedding, a lower bacterial burden in different organs, enhanced pathogen clearance and increased host survival. Additionally, the sustained innate activated IFNγ production could be attributed to iNOS-mediated signaling in Δ chiA mutant infected mice [ 53 ]. Bhat et al .…”

Small molecule inhibitors against PD-1/PD-L1 immune checkpoints and current methodologies for their development: a review

“…For instance, low proliferative capacity is a key character of T cell dysfunction [ 54 ], and cell proliferation is one of the most used assays to evaluate the biological functions of PD-1/PD-L1 inhibitors. In addition, the detection of IL-2 and IFN-γ are also widely used in the functional assay as IL-2 and IFN-γ are essential for T cell proliferation and activity, respectively [ 107 , 108 ]. Furthermore, signaling proteins involved in the PD-1/PD-L1 axis-mediated signaling transductions can be investigated to evaluate the biological effects of PD-1/PD-L1 inhibitors.…”