Presence of Inflammatory Group I and III Innate Lymphoid Cells in the Colon of Simian Immunodeficiency Virus-Infected Rhesus Macaques

Abstract

Chronic, low-grade, systemic, and mucosal inflammation correlates with increased morbidity and poor clinical outcomes among patients living with human immunodeficiency virus (HIV). These long-term complications are linked to the disruption of gastrointestinal (GI) tract epithelial barrier integrity and subsequent microbial translocation. However, the mechanisms responsible for these downstream effects of infection are unknown. Here, we demonstrate that during the disruption of the GI tract and increased microbial translocation, we find inflammatory cytokines (e.g., interferon gamma [IFN-γ] and tumor necrosis factor alpha [TNF-α]) produced by innate lymphoid cells (ILCs) located in the colon secondary to simian immunodeficiency virus (SIV) infection. To do this, we used viably cryopreserved colon cells from SIV-infected and uninfected rhesus macaque monkeys and determined the make-up of the ILC subpopulations and the cytokines they expressed constitutively. Our studies revealed that the interleukin-22 (IL-22)/IL-17-producing ILCS was not altered during SIV infection. However, the percentage of IFN-γ+ ILCs in infected colons was 5- to 10-fold higher than that in uninfected colons. ILCs from infected tissue that produced IFN-γ also expressed TNF-α and IL-22. The coexpression of inflammatory cytokines with IL-22 is linked to the ability of ILCs to coexpress T-bet and RORγT/Ahr. The expression of IFN-γ/TNF-α by ILCs and NK cells combined likely triggers a pathway that contributes to chronic mucosal inflammation, GI barrier breakdown, and microbial translocation within the context of SIV/HIV infection. IMPORTANCE There is a slow yet significant uptick in systemic inflammation secondary to HIV infection that has long-term consequences for the infected host. The systemic inflammation most likely occurs as a consequence of the disruption of the gut epithelial barrier, leading to the translocation of gut microbial products. This disruption may result from mucosal inflammation. Here, we show in an animal model of HIV that chronic SIV-infected gut contains innate lymphoid cells producing inflammatory cytokines.

Presence of Natural Killer B Cells in Simian Immunodeficiency Virus-Infected Colon That Have Properties and Functions Similar to Those of Natural Killer Cells and B Cells but Are a Distinct Cell Population

“…4C ), suggesting a noncanonical pathway of IL-18 production ( 37 ). Together, these findings suggest that NKB cells are a unique cellular source of the proinflammatory cytokine IL-18 but not IL-1β, which may lead to the downstream inflammation observed in the SIV-infected colon ( 28 , 38 ).…”

Natural killer cells play an important role in virus infection control: Antiviral mechanism, subset expansion and clinical application

“…Uninfected individuals produce high levels of IL-22, which is involved in the production of acute-phase proteins and results in chemokine receptor 5 (CCR5) phosphorylation, downregulation of CCR5 expression, and strongly decreased susceptibility of these cells to in vitro infection with a primary HIV-1 isolate [ 48 ]. In addition, IL-22 can also induce epithelial cells to produce antimicrobial molecules and IL-10 and act on DCs, T cells and B cells, promoting viral antigen presentation and reducing HIV reservoirs [ 18 , 49 , 50 ].…”

Evolution and Diversity of Immune Responses during Acute HIV Infection

“…OPEN ACCESS mother-to-child transmission (Hueber et al, 2020;Rahman et al, 2019). Groups 1 and 3 ILCs present in the GI tract during SIV infection potentially contribute to pro-inflammatory responses by producing higher levels of IFN-g, tumor necrosis factor (TNF)-a, and IL-22 during the breakdown of the epithelium (Cogswell et al, 2020); however, when these pro-inflammatory ILCs arise is unknown. Further work demonstrating functional roles for helper ILC subsets in T-cell-rich tissues is necessary to determine their roles in hyperacute HIV infection and the potential of targeting these cells in vaccines and treatments.…”