Innate Immune Activation of CD4 T Cells in Salmonella-Infected Mice Is Dependent on IL-18

Abstract

Production of IFN-γ by CD4 T cells is generally thought to be mediated by TCR triggering, however, Ag-nonspecific activation of effector CD8 T cells has been reported in infection models. In this study, we demonstrate that Ag-experienced CD4 T cells in the spleen of Salmonella-infected mice acquire the capacity to rapidly secrete IFN-γ in response to stimulation with bacterial lysate or LPS. This innate responsiveness of T cells was transient and most apparent during, and immediately following, active Salmonella infection. Furthermore, innate T cell production of IFN-γ in response to bacterial lysate or LPS was Ag independent and could be induced in Listeria-infected mice and in the absence of MHC class II expression. IL-18 was required for maximal innate responsiveness of CD4 T cells in Salmonella-infected mice and for optimal bacterial clearance in vivo. These data demonstrate that CD4 T cells acquire the capacity to respond to innate stimuli during active bacterial infection, a process that may contribute significantly to amplifying effector responses in vivo.

Contribution of Flagellin Pattern Recognition to Intestinal Inflammation duringSalmonella entericaSerotype Typhimurium Infection

“…Mice deficient for producing either IL-1␤ or IL-18 have enhanced susceptibility to serotype Typhimurium infection (52). IL-18, formerly known as IGIF (for IFN-␥ inducing factor) is a potent inducer of IFN-␥ production by T cells (42), which involves an innate mechanism that is antigen independent (63). Both IL-1␤ and IL-18 stimulate macrophages to produce CXC chemokines in vitro (47,77).…”

“…The IL-18/IFN-␥ axis has been implicated in amplifying inflammatory responses early after serotype Typhimurium infection in tissue (63). Interaction of serotype Typhimurium with phagocytes induces additional amplification mechanisms contributing to intestinal inflammation, including the IL-23/IL-17 axis (19,50).…”

T Cells Help To Amplify Inflammatory Responses Induced bySalmonella entericaSerotype Typhimurium in the Intestinal Mucosa

“…5). Since T cells are a potential source of IL-22, IL-17, and IFN-␥ (4,15,30), these data raised the possibility that genes whose mRNA levels were increased most dramatically during serotype Typhimurium infection may participate in a T-cell-mediated amplification of responses in tissue. The intestine is the largest reservoir of T cells in the human body, and this cell type is present abundantly throughout the lamina propria, thus making this cell type well suited for amplifying inflammatory responses.…”

“…4). Genes whose mRNA levels were increased most dramatically in serotype Typhimurium-infected tissue compared to mockinfected tissue included Il-22 and Ifn-␥ (Table 2), which encode two cytokines that can be produced by T cells (4,15,30). IL-22 and IFN-␥ synergize to increase the expression of nitric oxide synthase (iNOS) (40), and mRNA levels of these genes were also markedly increased after serotype Typhimurium infection (Table 2).…”

Blocking NF-κB Is Essential for the Immunotherapeutic Effect of Recombinant IL18 in Pancreatic Cancer

“…IL18 is produced mainly by immune cells and effectively enhances innate and adaptive immune responses (4). IL18 stimulates T cells and enhances Th1 immune responses (5)(6)(7). It also has antitumor activity in preclinical models.…”