The oral mucosa is a barrier site constantly exposed to rich and diverse commensal microbial communities, yet little is known of the immune cell network maintaining immune homeostasis at this interface. Characterization of the immune cell subsets at the gingival interface in health will provide important new insights into the cellular mechanisms operating to establish physiologic oral/periodontal immunity. We have performed a detailed characterization of the immune cell subsets of the oral cavity in a cohort of healthy/young adult subjects. For these studies, we evaluated more than 100 healthy volunteers in order to obtain biopsies from 50 healthy/young individuals to study the oral/gingival immunological network of oral health. We established protocols for isolation of mononuclear cells from tissue and employed multi-color flow cytometry to characterize in depth the immune cell subtypes in oral tissues. We focused our characterization on the gingival interface, a particularly vulnerable mucosal site, with a thin epithelial lining and constant exposure to the tooth-adherent biofilm. In health, we find a predominance of T cells, low numbers of B cells, a large presence of granulocytes/neutrophils, a sophisticated network of professional antigen-presenting cells (APCs), and a small population of innate lymphoid cells (ILCs) policing the gingival barrier. For comparison, we interrogated shifts in immune cell populations in periodontitis. In periodontitis, we observe increased inflammatory cells (particularly T cells and neutrophils) as well as a significant increase in Th17 cells (CD4 T cells secreting IL-17A). Collectively, our studies provide a view of the landscape of physiologic oral immunity and serve as a baseline for the characterization of local immunopathology. We have also developed techniques tailored to the study of oral tissue immunity in murine models. Specifically, we have developed protocols for the isolation and study of immune cells from murine gingival/oral tissues. Our protocol allows for the isolation of viable cells from gingiva, buccal mucosa and tongue and yields sufficient cells for a detailed phenotypic characterization of the immune cell populations resident in the oral cavity and gingiva, even at steady state (health). Our procedure also yields sufficient cells with high viability for use in functional studies, such as the assessment of cytokine secretion ex vivo. This combination of phenotypic and functional characterization of the gingival immune cell network will aid our future investigation of the mechanisms involved in oral immunity and periodontal homeostasis and advance our understanding of the mechanisms involved in local immunopathology. Our basic work has particularly focused on understanding mechanisms implicated in the development of Th17 immune responses at the gingival barrier. The development of Th17 responses at other barriers, such as the skin and gastrointestinal (GI) tract, has been linked to tissue-specific factors, particularly colonization by niche-specific commensals. However, little is known regarding the development of tissue immunity at the oral barrier. Consequently, it is not known how Th17 cells are induced in the oral environment. Our work reveals that Th17 cells may arise at the oral and periodontal barrier in the absence of commensal microbial communities, unlike regulation at other barriers. Through our studies we uncover physiologic damage from mastication as a critical tissue- specific trigger inducing Th17 dependent immunity at the oral barrier.

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Dental & Craniofacial Research
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Moutsopoulos, Niki M; Konkel, Joanne E (2018) Tissue-Specific Immunity at the Oral Mucosal Barrier. Trends Immunol 39:276-287
Konkel, J E; Moutsopoulos, N M (2018) Unique Tailoring of Th17 at the Gingival Oral Mucosal Barrier. J Dent Res 97:128-131
Abusleme, Loreto; Hong, Bo-Young; Hoare, Anilei et al. (2017) Oral Microbiome Characterization in Murine Models. Bio Protoc 7:
Dutzan, Nicolas; Abusleme, Loreto; Bridgeman, Hayley et al. (2017) On-going Mechanical Damage from Mastication Drives Homeostatic Th17 Cell Responses at the Oral Barrier. Immunity 46:133-147
Abusleme, L; Moutsopoulos, N M (2017) IL-17: overview and role in oral immunity and microbiome. Oral Dis 23:854-865
Dutzan, Nicolas; Konkel, Joanne E; Greenwell-Wild, Teresa et al. (2016) Characterization of the human immune cell network at the gingival barrier. Mucosal Immunol 9:1163-1172
Dutzan, Nicolas; Abusleme, Loreto; Konkel, Joanne E et al. (2016) Isolation, Characterization and Functional Examination of the Gingival Immune Cell Network. J Vis Exp :53736
Konig, Maximilian F; Abusleme, Loreto; Reinholdt, Jesper et al. (2016) Aggregatibacter actinomycetemcomitans-induced hypercitrullination links periodontal infection to autoimmunity in rheumatoid arthritis. Sci Transl Med 8:369ra176
Hajishengallis, George; Moutsopoulos, Niki M (2014) Etiology of leukocyte adhesion deficiency-associated periodontitis revisited: not a raging infection but a raging inflammatory response. Expert Rev Clin Immunol 10:973-5
Moutsopoulos, Niki M; Konkel, Joanne; Sarmadi, Mojgan et al. (2014) Defective neutrophil recruitment in leukocyte adhesion deficiency type I disease causes local IL-17-driven inflammatory bone loss. Sci Transl Med 6:229ra40

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