Brief Report: Inflammatory Colonic Innate Lymphoid Cells Are Increased During Untreated HIV-1 Infection and Associated With Markers of Gut Dysbiosis and Mucosal Immune Activation

Dillon, Stephanie M.; Castleman, Moriah J.; Frank, Daniel N.; Austin, Gregory L.; Gianella, Sara; Cogswell, Andrew; Landay, Alan; Barker, Edward; Wilson, Cara C.

doi:10.1097/qai.0000000000001523

Cited by 16 publications

(13 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[16][17][18][19] In the context of HIV, we have reported an increase in IFNγproducing NKp44+ CD56+ ILCs (a population of cells likely to include both NK cells and ILC1s) in the colonic mucosa of people living with HIV (PLWH) who are naïve to treatment. 20 Increases in IFNγ-producing and cytotoxic colonic ILCs (defined as CD3-NKp44+) were also reported in Rhesus macaques infected with SIV (the nonhuman primate model of HIV). 21,22 Conversely, in PLWH on anti-retroviral treatment with viral suppression the percentage of IFNγ-producing ILC1s in the gut mucosa were not different compared to uninfected controls.…”

Section: Introductionmentioning

confidence: 89%

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

et al. 2019

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Introductionmentioning

confidence: 89%

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

et al. 2019

Self Cite

View full text Add to dashboard Cite

show abstract

“…Similarly, reduced frequencies of IL-22/IL-17-producing ILCs during Simian Immunodeficiency Virus (SIV) infection (the non-human primate model of HIV) were noted (24–28). Furthermore, we and others have reported increased frequencies of IFNγ-producing ILCs both in people living with HIV (PLWH) who were not receiving anti-retroviral therapy (ART) (29) and during SIV infection (27). Since IFNγ alters epithelial tight junctions and upregulates epithelial cell expression of TNFα receptor which results in further epithelial cell damage (30, 31), increased frequencies of IFNγ-producing ILC3s may be an additional contributor to epithelial barrier breakdown.…”

Section: Introductionmentioning

confidence: 93%

“…When the epithelial barrier is compromised, translocation of gut-associated bacteria into the lamina propria (LP) exposes immune cells to bacteria of different species or magnitude than what these cells typically encounter in the healthy human gut (32, 33). We previously demonstrated that increased frequencies of colonic IFNγ-producing ILCs in PLWH correlated with alterations in mucosa-associated bacterial communities (dysbiosis), specifically with increased relative abundance of Gram-negative commensal Prevotella species (29). Understanding the bacteria-specific cytokine responses of ILC3s and the mechanisms by which protective or deleterious cytokines are produced are critical to determining the effect of ILC3s on gut homeostasis, not only for their role in enteric bacterial immunity, but also for their role in influencing epithelial cell function in disease states.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…pooled for same-day flow-based immunophenotyping [50,60] and the rest were frozen for later histology and transcriptomics. The study obtained comprehensive data including gut and PBMC IFNα and IFNβ transcript levels, plasma and gut viral loads, gut CD4+ T cell percentages (of CD45+ cells), myeloid activation (CD40 MFI in CD1c+ myeloid DCs), blood CD4+ T cell counts, markers of microbial translocation (sCD27, LPS, LTA), inflammation (CRP, IL6), and epithelial barrier dysfunction (iFABP) ( Table 1 and S11 Table) [38,50,[60][61][62][63]. We investigated how individual altered core ISGs (n = 126) and IFNβ-specific ISGs (n = 112) correlated with these clinically relevant parameters using linear regression models, after adjusting the data for age and gender.…”

Section: Plos Pathogensmentioning

confidence: 99%

Qualitative Differences Between the IFNα subtypes and IFNβ Influence Chronic Mucosal HIV-1 Pathogenesis

Guo

Shen²,

Kibbie

et al. 2020

PLoS Pathog

Self Cite

View full text Add to dashboard Cite

Brief Report: Inflammatory Colonic Innate Lymphoid Cells Are Increased During Untreated HIV-1 Infection and Associated With Markers of Gut Dysbiosis and Mucosal Immune Activation

Cited by 16 publications

References 52 publications

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

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

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

Qualitative Differences Between the IFNα subtypes and IFNβ Influence Chronic Mucosal HIV-1 Pathogenesis

Contact Info

Product

Resources

About