Abstract
SummaryThe spleen plays an important role in protective immunity to bloodborne pathogens. Macrophages and dendritic cells (DCs) in the spleen marginal zone capture microbial antigens to trigger adaptive immune responses. Marginal zone macrophages (MZMs) can also act as a replicative niche for intracellular pathogens, providing a platform for mounting the immune response. Here, we describe a role for RANK in the coordinated function of antigen-presenting cells in the spleen marginal zone and triggering anti-viral immunity. Targeted deletion of RANK results in the selective loss of CD169+ MZMs, which provide a niche for viral replication, while RANK signaling in DCs promotes the recruitment and activation of anti-viral memory CD8 T cells. These studies reveal a role for the RANKL/RANK signaling axis in the orchestration of protective immune responses in the spleen marginal zone that has important implications for the host response to viral infection and induction of acquired immunity.
Highlights
Activation of memory CD8 T cells is critical for protective immunity against intracellular pathogens such as viruses
Memory T cells have an intrinsic capacity to respond rapidly upon secondary infection (Zhang and Bevan, 2011), triggering of memory cells in secondary lymphoid organs still requires the activity of professional antigen-presenting cells such as dendritic cells (DCs) (Alexandre et al, 2016; Zammit et al, 2005). memory CD8 T cells (mCTLs) occupy frontline niches, such as the spleen marginal zone (MZ), whereas naive T cells are confined to the follicular T cell zone (Schenkel et al, 2014)
These studies suggest that CD169+ MZ macrophages (MZMs), as well as DCs, can have important roles in CD8 T cell responses and cell-mediated immunity to bloodborne pathogens
Summary
Activation of memory CD8 T cells (mCTLs) is critical for protective immunity against intracellular pathogens such as viruses. The spleen MZ is populated by antigen-presenting cells, including macrophages and DCs, that are strategically placed to capture pathogens and antigens from the blood (Martinez-Pomares and Gordon, 2012). In the context of infection, CD169+ MZ macrophages (MZMs) can be permissive for certain intracellular pathogens and form a restricted niche for replication, providing a platform for mounting both cell-mediated and humoral immune responses (Honke et al, 2011). CD169 itself has been shown to be a receptor for virus entry through binding to gangliosides in the viral envelope (Hammonds et al, 2017; Sewald et al, 2015) These studies suggest that CD169+ MZMs, as well as DCs, can have important roles in CD8 T cell responses and cell-mediated immunity to bloodborne pathogens. The molecular mechanisms that regulate the coordinated function of these antigen-presenting cells and help orchestrate the protective immune response remain poorly understood
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