Commensal and Pathogenic Bacteria Indirectly Induce IL-22 but Not IFNγ Production From Human Colonic ILC3s via Multiple Mechanisms

Abstract

Innate lymphoid cells (ILCs) are a diverse family of cells that play critical roles in mucosal immunity. One subset of the ILC family, Group 3 ILCs (ILC3s), has been shown to aid in gut homeostasis through the production of IL-22. IL-22 promotes gut homeostasis through its functional effect on the epithelial barrier. When gut epithelial barrier integrity is compromised, such as in Human Immunodeficiency Virus (HIV) infection and inflammatory bowel disease (IBD), microbes from the gut lumen translocate into the lamina propria, inducing a multitude of potentially pathogenic immune responses. In murine models of bacterial infection, there is evidence that bacteria can induce pro-inflammatory IFNγ production in ILC3s. However, the impact of diverse translocating bacteria, particularly commensal bacteria, in dictating IFNγ versus IL-22 production by human gut ILC3s remains unclear. Here, we utilized an in vitro human lamina propria mononuclear cell (LPMC) model to evaluate ILC3 cytokine production in response to a panel of enteric Gram-positive and Gram-negative commensal and pathogenic bacteria and determined potential mechanisms by which these cytokine responses were induced. The percentages of IL-22-producing ILC3s, but not IFNγ-producing ILC3s, were significantly increased after LPMC exposure to both Gram-positive and Gram-negative commensal or pathogenic bacterial stimuli. Stimulation of IL-22 production from ILC3s was not through direct recognition of bacterial antigen by ILC3s, but rather required the help of accessory cells within the LPMC population. CD11c+ myeloid dendritic cells generated IL-23 and IL-1β in response to enteric bacteria and contributed to ILC3 production of IL-22. Furthermore, ligation of the natural cytotoxicity receptor NKp44 on ILC3s in response to bacteria stimulation also significantly increased the percentage of IL-22-producing ILC3s. Overall, these data demonstrate that human gut microbiota, including commensal bacteria, indirectly modulate colonic ILC3 function to induce IL-22, but additional signals are likely required to induce IFNγ production by colonic ILC3s in the setting of inflammation and microbial translocation.

Dietary cellulose induces anti-inflammatory immunity and transcriptional programs via maturation of the intestinal microbiota

“…These cells start to secrete IL-22 after stimulation with enteric commensals. 60 It is subject of further studies to disclose which IL-22-producing cell type is affected by A. finegoldii .…”

Enteric bacteria induce IFNγ and Granzyme B from human colonic Group 1 Innate Lymphoid Cells

“…46 Here, two of the Gram-negative commensals tested (P. stercorea and A. junii) reside within genera of bacteria that are reported to contain pathobionts, 47,48 and thus members of these genera may induce inflammation in the setting of epithelial barrier damage. Interestingly, we have previously shown that these exact species can also induce IL-22 production by human colonic ILC3s, 49 which is a cytokine with a role in epithelial barrier maintenance and regulation of intestinal health. However, it is important to note that while we did investigate the effect of four commensal bacteria representing four different phyla on the induction of cytokine production by Group 1 ILCs, we acknowledge that there are a multitude of different bacterial species in the human gut and therefore we cannot conclude that all bacteria would elicit similar responses in Group 1 ILCs.…”

“…A release was signed by all patients undergoing surgery to allow unrestricted use of discarded tissue. LPMCs were isolated from tissue samples as previously described 49,55,56 and stored in liquid nitrogen until use.…”

Microbiota-Dependent Effects of IL-22

“…On the one hand, Castleman and colleagues showed that both Gram-positive and -negative commensal bacteria induced the expression of IL-22 by ILC3s. This IL-22 production by ILC3s was not mediated through direct recognition of bacteria, but rather mediated indirectly by myeloid dendritic cells (mDCs) and is partly dependent on IL-23 and IL-1β [ 39 ]. On the other hand, another report showed that Bacillus anthracis can downregulate IL-22 in ILC3s via an IL-23 mediated MAPK signaling pathway [ 40 ].…”