Interleukin-7 Produced by Intestinal Epithelial Cells in Response to Citrobacter rodentium Infection Plays a Major Role in Innate Immunity against This Pathogen

Abstract

bInterleukin-7 (IL-7) engages multiple mechanisms to overcome chronic viral infections, but the role of IL-7 in bacterial infections, especially enteric bacterial infections, remains unclear. Here we characterized the previously unexplored role of IL-7 in the innate immune response to the attaching and effacing bacterium Citrobacter rodentium. C. rodentium infection induced IL-7 production from intestinal epithelial cells (IECs). IL-7 production from IECs in response to C. rodentium was dependent on gamma interferon (IFN-␥)-producing NK1.1 ؉ cells and IL-12. Treatment with anti-IL-7R␣ antibody during C. rodentium infection resulted in a higher bacterial burden, enhanced intestinal damage, and greater weight loss and mortality than observed with the control IgG treatment. IEC-produced IL-7 was only essential for protective immunity against C. rodentium during the first 6 days after infection. An impaired bacterial clearance upon IL-7R␣ blockade was associated with a significant decrease in macrophage accumulation and activation in the colon. Moreover, C. rodentium-induced expansion and activation of intestinal CD4 ؉ lymphoid tissue inducer (LTi) cells was completely abrogated by IL-7R␣ blockade. Collectively, these data demonstrate that IL-7 is produced by IECs in response to C. rodentium infection and plays a critical role in the protective immunity against this intestinal attaching and effacing bacterium. Citrobacter rodentium is a mouse extracellular enteric pathogen that mimics human-enteropathogenic Escherichia coli (EPEC) and enterohemorrhagic E coli (EHEC). These bacterial pathogens attach intimately to intestinal epithelium and cause subcellular attaching and effacing lesions, which lead to severe diarrhea, vomiting, and fever, with high rates of fatality (1). C. rodentium infection of mice causes epithelial hyperplasia in the colon and cecum, goblet cell loss, and mucosal infiltration with macrophages, lymphocytes, and neutrophils (2). Therefore, this is an ideal model to dissect how immune cells interact with gut epithelial pathogens. The innate immune cells, including macrophages, dendritic cells (DCs), natural killer (NK) cells, neutrophils, and innate lymphoid cells (ILCs) have been shown to play an essential role in the clearance of C. rodentium infection (3-6). Moreover, the adaptive immune cells, mostly T and B cells, are also required for the clearance of this pathogen (7,8). Furthermore, the cytokines interleukin-6 (IL-6), IL-12, IL-17, IL-22, IL-23, and gamma interferon (IFN-␥) are upregulated in the colon tissues of C. rodentium-infected mice and are necessary for an effective immune defense against this pathogen (3-5, 7, 9).IL-7 is a stroma-derived cytokine that can be secreted by fetal liver cells, stromal cells in the bone marrow and thymus, and intestinal epithelial cells (IECs) (10). IL-7 acts on various cells through its receptor, a heterodimer consisting of an alpha-chain (IL-7R␣) and the common cytokine receptor gamma chain. The IL-7 receptor is expressed on lymphoid T and B precursors...

IL-7 receptor influences anti-TNF responsiveness and T cell gut homing in inflammatory bowel disease

“…It showed also that IL-7Rα blockade seems to induce a transcriptional program of T cell exhaustion (e.g., PD-1 and TIM-3 expression), which could also explain the inhibition of IFN-γ secretion. Close linkage between IL-7 and IFN-γ secretion has been previously proposed, since IL-7 production by human intestinal epithelial cells in response to Citrobacter rodentium was described to be dependent on IFN-γ (71) and others demonstrated that IFN-γ directly enhanced IL7 mRNA expression in intestinal epithelial cells (80). Finally, Shalapour et al (23) suggested a feedback loop in which commensal bacteria drive IFN-γ production by lymphocytes, which in turn promotes epithelial cell IL-7 production and IL-7-dependent local survival of lymphocytes.…”

“…While we found significantly increased IL7 cytokine expression by RT-qPCR in our local cohort, IL7 cytokine expression assessed in previous studies was found to be significantly increased in only 2 of 7 data sets. In response to commensal microflora invasion, gut epithelial cells were shown to produce IL-7 (23,71,72) and to regulate the proliferation of intestinal mucosal lymphocytes (38) as well as production of inflammatory cytokines by human ILC3s also expressing IL-7R (73). Thus, it is conceivable that high IL7 expression in the colon is more related to bacterial tissue invasion, while our results reproducibly show an IL7R and IL-7R signaling signature accumulation that is associated with clinical IBD status and nonresponsiveness to anti-TNF therapy.…”

Ginseng Berry Extract Attenuates Dextran Sodium Sulfate-Induced Acute and Chronic Colitis

“…Sections were then stained with hematoxylin and eosin (H & E) and examined for tissue damage. Colon sections were evaluated using pathology scores for evidence of inflammatory damage, as described previously [ 27 ].…”

“…The LP single cell suspensions were prepared as described in detail previously [ 27 ]. In brief, colons were isolated and washed twice in ice-cold PBS.…”

Interleukin-7 Receptor Alpha in Innate Lymphoid Cells: More Than a Marker

“…IL-7 is mainly produced in primary lymphoid tissues such as the bone marrow and thymic stromal cells where immune cell development occurs (26,85). However, this cytokine is also produced in secondary lymphoid organs and can be induced in skin, lung, intestinal epithelial cells, and liver as shown by fluorescence microscopy of IL-7 reporter mice and ELISA (28,29,32,85,86). The extent of our knowledge on IL-7 and ILC function is based on a series of in vitro experiments.…”