Abstract
Our understanding of innate immune responses in human rectal mucosal tissues (RM) and their contributions to promoting or restricting HIV transmission is limited. We defined the RM composition of innate and innate-like cell subsets, including plasmacytoid dendritic cells; CD1c + myeloid DCs; neutrophils; macrophages; natural killer cells (NK); Marginal Zone-like B cells (MZB); γδ T cells; and mucosal-associated invariant T cells in RM from 69 HIV-negative men by flow cytometry. Associations between these cell subsets and HIV-1 replication in ex vivo RM explant challenge experiments revealed an inverse correlation between RM-NK and p24 production, in contrast to a positive association between RM-MZB and HIV replication. Comparison of RM and blood-derived MZB and NK illustrated qualitative and quantitative differences between tissue compartments. Additionally, 22 soluble molecules were measured in a subset of explant cultures (n = 26). Higher production of IL-17A, IFN-γ, IL-10, IP-10, GM-CSF, sFasL, Granzyme A, Granzyme B, Granulysin, and Perforin following infection positively correlated with HIV replication. These data show novel associations between MZB and NK cells and p24 production in RM and underscore the importance of inflammatory cytokines in mucosal HIV infection, demonstrating the likely critical role these innate immune responses play in early mucosal HIV replication in humans.
Highlights
Our understanding of innate immune responses in human rectal mucosal tissues (RM) and their contributions to promoting or restricting HIV transmission is limited
In order to define the innate and innate-like immune environment within the RM, we first quantified via flow cytometry the following subsets within rectal tissues after collagenase digestion from HIV-negative, sexually transmitted infection (STI)-negative males as a percentage of total CD45 + cells (Fig. 1A–C): neutrophils, macrophages, CD1c + myeloid dendritic cells, plasmacytoid dendritic cells, natural killer cells (NK), and Marginal Zone-like B cells (MZB) cells (n = 69), as well as Mucosal associated invariant T cells (MAIT) and γδ T cells (n = 85)
Both MZB (Kruskal–Wallis, p < 0.0001, all comparisons) and NK (Kruskal–Wallis, p < 0.0001, all comparisons, except γδ T cells, p = 0.009) were the most abundant cell types quantified with MZB values ranging from 1% to 26.4% of all CD45 + cells and NK values ranging from 1% to 12.2%. γδ T cells were the only additional cell subset regularly present at > 1% of CD45 + cells
Summary
Our understanding of innate immune responses in human rectal mucosal tissues (RM) and their contributions to promoting or restricting HIV transmission is limited. We defined the RM composition of innate and innate-like cell subsets, including plasmacytoid dendritic cells; CD1c + myeloid DCs; neutrophils; macrophages; natural killer cells (NK); Marginal Zone-like B cells (MZB); γδ T cells; and mucosal-associated invariant T cells in RM from 69 HIV-negative men by flow cytometry. Macrophages, dendritic cells, and B cells isolated from peripheral blood are able to mediate trans infection, resulting in p24 accumulation orders of magnitude greater than levels associated with direct cis infection of CD4 + T cells[14,15] This process could be highly relevant during mucosal transmission, where APC have been implicated as actors in the first stages of intravaginal infection[16,17]. A unique subset of B cells that are considered ‘innate-like’, Marginal Zone-like B cells (MZB), are found within mucosal and epithelial barriers in humans, including the RM, and have been recently associated with HIV transmission and pathogenesis in humans[18,19,20,21,22,23]
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