Multi‐functional plasmacytoid dendritic cells redistribute to gut tissues during simian immunodeficiency virus infection

Abstract

SummaryThe objective of this study was to determine the systemic effects of chronic simian immunodeficiency virus (SIV) infection on plasmacytoid dendritic cells (pDCs). pDCs play a critical role in antiviral immunity, but current data are conflicting on whether pDCs inhibit HIV/SIV replication, or, alternatively, contribute to chronic immune activation and disease. Furthermore, previous pDC studies have been complicated by incomplete descriptions of generalized depletion during HIV/SIV infection, and the effects of infection on pDCs outside peripheral blood remain unclear. In scheduled-sacrifice studies of naive and chronically SIV-infected rhesus macaques we evaluated the distribution and functionality of pDCs in multiple tissues using surface and intracellular polychromatic flow cytometry. As previously observed, pDCs were reduced in peripheral blood and spleens, but were also depleted in non-lymphoid organs such as the liver. Interestingly, pDCs accumulated up to fourfold in jejunum, colon and gut-draining lymph nodes, but not in peripheral lymph nodes. Most unexpectedly, SIV infection induced a multi-functional interferon-a, tumour necrosis factor-a, and macrophage inflammatory protein-1b cytokine secretion phenotype, whereas in normal animals these were generally distinct and separate functions. Herein we show a systemic redistribution of pDCs to gut tissues and gut-draining lymph nodes during chronic SIV infection, coupled to a novel multi-functional cytokine-producing phenotype. While pDC accumulation in the mucosa could aid in virus control, over-production of cytokines from these cells could also contribute to the increased immune activation in the gut mucosa commonly associated with progressive lentivirus infections.

Plasmacytoid dendritic cells of the gut: Relevance to immunity and pathology

“…These data support the hypothesis that the loss of pDCs in the periphery was a result of their redistribution into the gut. In further support of this, Li and colleagues have demonstrated a fourfold increase in pDC accumulation in jejunum, colon, and gut-draining LNs of SIV infected rhesus macaques [151]. At the same time there was no pDC accumulation in the liver and peripheral LNs.…”

Simian Immunodeficiency Virus Infection and Mucosal Immunity

“…Further, in SIV-infected macaques, pDCs rapidly increase in blood, then rapidly decline to less than 50% of baseline levels by peak viremia and remain low throughout SIV infection (Reeves and Fultz, 2007;Brown et al, 2007). However, recent studies suggest that these cells are simply being redistributed to the gut (rather than eliminated) as reflected by marked accumulations of pDCs in the gut in SIV-infected macaques (Li et al, 2013a;Reeves et al, 2012). However, and as above, recent findings suggest that pDC activation and IFN-α responses may not be wholly beneficial to the HIV/SIV-infected host and may be detrimental by promoting immune activation and/ or bystander apoptosis specifically within intestinal tissues.…”

Innate Immunity in Simian Immunodeficiency Virus Infection

“…Interestingly, studies of acute pathogenic SIV infection in macaques have demonstrated a transient increase of pDCs in peripheral blood after rapid egress from the bone marrow, followed by depletion of circulating pDCs and accumulation of apoptotic pDCs in lymph nodes [57,120]. Furthermore, recent evidence from multiple laboratories has shown that pDCs are not necessarily depleted during pathogenic SIV infection, but rather, accumulate in large numbers in the GI tract [124][125][126]. Of note, this phenomenon appears to be absent in nonpathogenic SIV infections.…”