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

Abstract

Group 1 Innate Lymphoid Cells (which include Natural Killer cells and ILC1s) aid in gut antibacterial defense through the production of IFNγ, which is critical for mobilizing protective responses against enteric pathogens. When intestinal epithelial barrier integrity is compromised, commensal bacteria are likely to translocate from the gut lumen into the lamina propria. Few studies have addressed the mechanisms by which commensal bacteria impact the function of gut Group 1 ILCs, especially ILC1s. Utilizing an in vitro human colonic lamina propria mononuclear cell (LPMC) model, we evaluated Group 1 ILC cytokine and cytolytic protein production in response to a panel of enteric Gram-positive and Gram-negative commensal and pathogenic bacteria. IFNγproduction by NK cells and ILC1s was significantly increased after LPMC exposure to Gramnegative commensal or pathogenic bacteria, but not after exposure to the Gram-positive bacteria commensals tested. Stimulation of IFNγ production from Group 1 ILCs was not through direct recognition of bacteria by NK cells or ILC1s, but rather required accessory cells within the LPMC population. Myeloid dendritic cells generated IL-12p70, IL-18, and IL-1β upon exposure to enteric bacteria and these cytokines contributed to Group 1 ILC production of IFNγ. Furthermore, Gramnegative commensal or pathogenic bacteria induced significant expression of Granzyme B in NK cells and ILC1s. Overall, these data demonstrate that some enteric commensal bacteria indirectly induce inflammatory cytokine production and cytolytic protein expression from human colonic Group 1 ILCs, a process which could contribute to inflammation in the setting of microbial translocation.

Regulation of Human Innate Lymphoid Cells in the Context of Mucosal Inflammation

“…In response to the enhanced release of IL-12p70, IL-18, and IL-1β by local myeloid dendritic cells (DCs), intestinal ILC1s are able to secrete increased levels of the pro-inflammatory cytokines IFN-γ and TNF-α and thus relevantly support the mucosal immune response against bacterial intruders. This was true for gram-negative commensals and pathogens, e.g., Acinetobacter junii and Salmonella typhimurium, as shown in in vitro cocultures of human ILC1s and lamina propria mononuclear cells (LPMCs) (79). Without proper regulation of this response, chronic inflammation can be established.…”

Innate lymphoid cells are double‐edged swords under the mucosal barrier

“…ILC1s are predominantly distributed within the intestinal lamina propria and participate in resisting bacteria by secreting IFN‐γ 38 . After exposure to pathogenic bacteria, lamina propria mononuclear cells (LPMC) activate ILC1s to release IFN‐γ, which in turn resist bacterial invasion 79 . Besides, IL‐22‐secreting ILC3s promote the secretion of antimicrobial peptides, lipocalin and mucus to prevent the invasion of bacteria 80 .…”

Innate Lymphoid Cells: Important Regulators of Host–Bacteria Interaction for Border Defense

“…ILC1, including NK cells, are mainly involved in the defense against tumors and intracellular pathogens such as viruses. Information about the interaction of ILC1 with bacteria had so far been limited, but has become better understood because of several recent reports [ 1 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 ]. A human study in which colonic lamina propria-derived ILC1 were exposed to commensal gut bacteria, interestingly showed that only Gram-negative bacteria induced the production of IFN-γ.…”

“…A human study in which colonic lamina propria-derived ILC1 were exposed to commensal gut bacteria, interestingly showed that only Gram-negative bacteria induced the production of IFN-γ. CD11c + myeloid dendritic cells (mDC) mediate ILC1 stimulation by releasing the cytokines IL-12p70, IL-18, and IL-1β, resulting in ILC1-derived production of granzyme B and IFN-γ [ 35 ]. Moreover, in vitro experiments indicated that IFN-γ could promote the translocation of Escherichia coli (E.coli) due to cytokine-dependent tight junction disruption [ 36 ].…”

“…Loss of NK cells and the subsequent absence of protective IFN-γ secretion has been shown to increase susceptibility in the murine S. typhimurium infection model [ 44 , 47 ]. The study by Castleman et al [ 35 ] further indicated that the in vitro exposure of commensal Gram-negative and pathogenic S. typhimurium to human colonic lamina propria cells led to increased IFN-γ expression by ILC1 and NK cells, which was mediated by the cytokines IL-12p70, IL-18, and IL-1β [ 22 ].…”