A role for mucosal IL-22 production and Th22 cells in HIV-associated mucosal immunopathogenesis

Abstract

Interleukin-22 (IL-22) is a cytokine with epithelial reparative and regenerative properties that is produced by Th22 cells and by other immune cell subsets. Therefore, we explored the hypothesis that disruption of the gut barrier during HIV infection involves dysregulation of these cells in the gastrointestinal mucosa. Sigmoid IL-22-producing T cell and Th22 cells were dramatically depleted during chronic HIV infection, epithelial integrity was compromised, and microbial translocation was increased. These alterations were reversed after long-term antiretroviral therapy. While all mucosal IL-22-producing T-cell subsets were also depleted very early during HIV infection, at these early stages IL-22 production by non-T-cell populations (including NKp44+ cells) was increased and gut epithelial integrity was maintained. Circulating Th22 cells expressed a higher level of the HIV co-receptor/binding molecules CCR5 and α4β7 than CD4+ T-cell subsets in HIV-uninfected participants, but this was not the case after HIV infection. Finally, recombinant IL-22 was protective against HIV and tumor necrosis factor-α-induced gut epithelial damage in a validated in vitro gut epithelial system. We conclude that reduced IL-22 production and Th22 depletion in the gut mucosa are important factors in HIV mucosal immunopathogenesis.

The comparison of Th1, Th2, Th9, Th17 and Th22 cytokine profiles in acute and chronic HIV-1 infection

“…IL-22 is important for the maintenance of the intestinal mucosa integrity. It has been previously shown that chronic HIV infection leads to the exhaustion of Th22 cell subset [30]. However, our study showed increased concentrations of IL-22 in chronic HIV-1 infection and this issue requires further investigations.…”

Mucosal Th17 Cell Function Is Altered during HIV Infection and Is an Independent Predictor of Systemic Immune Activation

“…However, increased systemic microbial translocation (i.e., plasma LPS levels) was only apparent during chronic HIV infection, whereas a dramatic impairment of Th17 function was apparent very early after HIV acquisition. We hypothesize that this delayed impact of Th17 functional impairment on mi- crobial translocation may be because a loss of epithelial integrity is also needed for microbial translocation to occur, and this integrity is only compromised later in HIV infection, coincident with the loss of mucosal IL-22 production capacity (2,4). Although the polyfunctional capacity of mucosal Th17 cells was reduced during untreated HIV infection, this was not directly associated with microbial translocation or systemic immune activation.…”

“…Th17 cells were defined as IL-17a + CD4 T cells, and Tregs were defined as FOXP3 and CD25 dually positive CD4 T cells. The absolute number of gut cells was determined by multiplying the percentage of live lymphocytes, determined by flow cytometry, by the number of gut cells/g of tissue, as previously described (2,34). Th17 cell polyfunctionality analysis was generated by Boolean gating analysis using FlowJo software, and a minimum event number of 50 was set for Th17 polyfunctionality analyses.…”

“…The progression of HIV and SIV infection is mediated by a rapid depletion of gastrointestinal CD4 T cells, followed by a deterioration of the gut epithelium and increased microbial translocation (2)(3)(4). IL-17a-producing Th17 cells are an important subset of CD4 T cells that maintains the gut mucosa by inducing the proliferation of epithelial cells (5), promoting antibacterial defensin production (6), and recruiting neutrophils in the context of bacterial invasion (7,8).…”

Mucosal Immune Regulation: Does it Help Thwart HIV?

“…Th17 and Th22 populations are involved in the generation of immune responses to microbial pathogens at mucosal surfaces and play a critical role in normal barrier homeostasis [18,62] (reviewed by [63]. In HIV infection, Th17 and Th22 cells are depleted more severely than the bulk CD4 + T cell population in the intestinal compartment [64,65]. The strong depletion of these cells is associated with the development of malabsorption and nutriment complications in rhesus macaques [66] and with a decreased expression of markers regulating barrier integrity and intestinal function [67,68].…”