Identification of an innate T helper type 17 response to intestinal bacterial pathogens

Abstract

Interleukin 17 (IL-17) is a central cytokine implicated in inflammation and antimicrobial defense. After infection, both innate and adaptive IL-17 responses have been reported, but the type of cells involved in innate IL-17 induction, as well as their contribution to in vivo responses, are poorly understood. Here we found that Citrobacter and Salmonella infection triggered early IL-17 production, which was crucial for host defense and was mediated by CD4(+) T helper cells. Enteric innate T helper type 17 (iT(H)17) responses occurred principally in the cecum, were dependent on the Nod-like receptors Nod1 and Nod2, required IL-6 induction and were associated with a decrease in mucosal CD103(+) dendritic cells. Moreover, imprinting by the intestinal microbiota was fully required for the generation of iT(H)17 responses. Together, these results identify the Nod-iT(H)17 axis as a central element in controlling enteric pathogens, which may implicate Nod-driven iT(H)17 responses in the development of inflammatory bowel diseases.

Constitutive induction of intestinal Tc17 cells in the absence of hematopoietic cell‐specific MHC class II expression

“…The kinetics at which MHCII −/− →WT mice succumbed to the infection, with the first animal dying as early as 3 days p.i., further suggests that CD4 + T cells play a critical protective role in the early phases of infection with C. rodentium in the chimeras. We previously found that the intestinal microbiota was essential for the generation of an iTh17 response to an enteric bacterial pathogen, as this response was completely blunted in germ-free mice infected with Salmonella Typhimurium [23]. Here, we now provide evidence that MHCII is also required for the induction of early lamina propria Th17 responses to bacterial infection, which strongly suggests that specific antigens are needed to either prime or drive this response.…”

“…In particular, it is unclear if specific pathogenderived and/or microbiota-derived antigens are required to prime Th17 cells. In vitro studies suggest that the induction of a specific network of cytokines is sufficient for the activation of these cells [26]; however, our previous study identified a crucial role for the intestinal microbiota in promoting innate Th17 responses in the cecum of Salmonella-infected mice [23]. This suggests a key role for specific antigens in iTh17 induction in the intestine following bacterial infection.…”

Muramyl dipeptide responsive pathways in Crohn’s disease: from NOD2 and beyond

“…Thus, stimulation of human dendritic cells (DCs) with MDP has been shown to enhance NOD2-mediated production of IL-1β and IL-23 which in turn promotes IL-17 production by memory Th17 cells [64]. Moreover, a recently study reported by Geddes et al [65] suggests a specific role for NOD2 in the early innate response. The authors used a mouse model in identifying an early NOD2-dependent Th17 response restricted to the acute phase of infections after treatment with pathogens, including Salmonella Typhimurium and Citrobacter rodentium.…”

“…The authors used a mouse model in identifying an early NOD2-dependent Th17 response restricted to the acute phase of infections after treatment with pathogens, including Salmonella Typhimurium and Citrobacter rodentium. NOD2 expression by myeloid and somatic cells was a crucial factor in recognition of pathogens and thereby for a functional early Th17 response [65]. Further, impaired acute Th17 responses in Nod2 knockout mice were associated with unaffected colonic colonization and diminished colonic inflammation at early stages, which is in contrast to an enhanced tissue destruction and increased bacterial translocation later in the course of the disease, indicating a protective role of the acute Th17 response in infection control [65].…”

“…NOD2 expression by myeloid and somatic cells was a crucial factor in recognition of pathogens and thereby for a functional early Th17 response [65]. Further, impaired acute Th17 responses in Nod2 knockout mice were associated with unaffected colonic colonization and diminished colonic inflammation at early stages, which is in contrast to an enhanced tissue destruction and increased bacterial translocation later in the course of the disease, indicating a protective role of the acute Th17 response in infection control [65]. However, treatment with human anti-IL-17A monoclonal antibodies has been revealed to be without any clinical effects in CD [66].…”