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Abstract
Despite the fact that the majority of human pathogens are transmitted across mucosal surfaces, including the oral mucosae, oral immunity is poorly understood. Furthermore, because the normal flora of the oral cavity is vast and significantly diverse, host immunity must balance a complex system of tolerance and pathogen recognition. Due to the rapid recognition and response to pathogens, the innate immune system, including natural killer (NK) cells, likely plays a critical role in mediating this balance. Because logistical and ethical restraints limit access to significant quantities of human mucosal tissues, non-human primate models offer one of the best opportunities to study mucosal NK cells. In this study we have identified both classical NK cells, as well as innate lymphoid cells (ILCs) in tonsillar and buccal tissues and oral-draining lymph nodes. Identified by mutually exclusive expression of NKG2A and NKp44, NK cells, and ILCs in the oral mucosa are generally phenotypically and functionally analogous to their gut counterparts. NKG2A+ NK cells were more cytotoxic while NKp44+ ILCs produced copious amounts of IL-17 and TNF-α. However, in contrast to gut, oral NK cells and ILCs both produced large quantities of IFN-γ and the beta-chemokine, MIP-1β. Also in contrast to what we have previously found in gut tissues of SIV-infected macaques, we found no reduction in NK cells during chronic SIV infection, but rather an expansion of ILCs in oral-draining lymph nodes and tonsils. These data suggest that the lentivirus-induced depletion of the NK cell/ILC compartment in the gut may be absent in the oral mucosa, but the inherent differences and SIV-induced alterations are likely to have significant impact on preventing oral opportunistic infections in lentiviral disease. Furthermore, these data extend our understanding of the oral innate immune system in general and could aid future studies evaluating the regulation of both normal oral flora and limiting transmission of oral mucosal pathogens.
Highlights
Natural killer (NK) cell research in humans and mice has focused heavily on blood and secondary lymphoid organs, more recent reports have provided convincing evidence for a diverse natural killer (NK) cell repertoire in the gastrointestinal (GI) and female reproductive tracts
To further confirm the identity of oral NK cells, we analyzed expression of NKG2D and NKp30, which were found at high levels on NKG2A+ NK cells, but were dim to negative on NKp44+ innate lymphoid cells (ILCs) (Figure 1B)
NK cells were ∼10-fold less frequent in tonsils and oral lymph nodes (OLN) and mesenteric lymph nodes (MLN)
Summary
Natural killer (NK) cell research in humans and mice has focused heavily on blood and secondary lymphoid organs, more recent reports have provided convincing evidence for a diverse NK cell repertoire in the gastrointestinal (GI) and female reproductive tracts. Little is known about NK cells in distal mucosal tissues, such as the oral mucosa. Bulk NK cells in the labial and oropharyngeal mucosae are dense, constituting up to 40% of total lymphocytes and are primarily located submucosally and in the lamina propria, as indicated by immunohistochemistry (de Repentigny et al, 2004; Challacombe and Naglik, 2006; Zancope et al, 2010). NK cells have been shown to accumulate both intratumorally and peritumorally during oral cavity and lip squamous cell carcinomas (Zancope et al, 2010)
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