Characterization of the human immune cell network at the gingival barrier
Open accessAbstract
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. We have performed a detailed characterization of the immune cell subsets of the oral cavity in a large cohort of healthy subjects. We focused our characterization on the gingival interface, a particularly vulnerable mucosal site, with thin epithelial lining and constant exposure to the tooth adherent biofilm. In health, we find a predominance of T cells, minimal 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. We further characterize cellular subtypes in health and interrogate shifts in immune cell populations in the common oral inflammatory disease periodontitis. In disease, we document an increase in neutrophils and an upregulation of interleukin-17 (IL-17) responses. We identify the main source of IL-17 in health and Periodontitis within the CD4(+) T-cell compartment. Collectively, our studies provide a first view of the landscape of physiologic oral immunity and serve as a baseline for the characterization of local immunopathology.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The oral cavity is the first organ to encounter ingested food and drink, exogenous microbes, allergens, and antigens before they pass further into the gastrointestinal and/or respiratory tracts.
“As the gatekeeper of the alimentary canal, the oral cavity is the first organ to encounter ingested food and drink, exogenous microbes, allergens, and antigens before they pass further into the gastrointestinal and/or respiratory tracts.54”
From The oral microbiome: Role of key organisms and complex networks in oral health and disease (2021) · cites this paper as [54]
In an additional study, homeostatic T-helper 17 cells were induced by mechanical stimuli in a microbiome-independent manner, whereas periodontitis-associated T-helper 17 cells accumulated in a microbiome-dependent manner and required both interleukin-6 and interleukin-23.
“homeostatic T‐helper 17 cells were found to be induced by mechanical stimuli in a microbiome‐independent manner, whereas periodontitis‐associated T‐helper 17 cells were found to accumulate in a microbiome‐dependent manner and to require both interleukin‐6 and interleukin‐23.”
From The oral microbiome: Role of key organisms and complex networks in oral health and disease (2021) · cites this paper as [54]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Fate Mapping Reveals Origins and Dynamics of Monocytes and Tissue Macrophages under Homeostasis
Yona, S., Kim, K.-W., Wolf, Y., Mildner, A., Varol, D., Breker, M., Strauss-Ayali, D., Viukov, S., Guilliams, M., Misharin, A., et al. (2013) · Immunity · doi:10.1016/j.immuni.2012.12.001 · Cited by 3,245 · see citing works
Bacterial Community Variation in Human Body Habitats Across Space and Time
Costello, E. K., Lauber, C. L., Hamady, M., Fierer, N., Gordon, J. I., & Knight, R. (2009) · Science · doi:10.1126/science.1177486 · Cited by 3,231 · see citing works
Defining the normal bacterial flora of the oral cavity
Aas, J. A., Paster, B. J., Stokes, L. N., Olsen, I., & Dewhirst, F. E. (2005) · Journal of Clinical Microbiology · doi:10.1128/jcm.43.11.5721-5732.2005 · Cited by 3,092 · see citing works
Central Memory and Effector Memory T Cell Subsets: Function, Generation, and Maintenance
Sallusto, F., Geginat, J., & Lanzavecchia, A. (2004) · Annual Review of Immunology · doi:10.1146/annurev.immunol.22.012703.104702 · Cited by 3,067 · see citing works
Periodontitis: from microbial immune subversion to systemic inflammation
Hajishengallis, G. (2015) · Nature Reviews Immunology · doi:10.1038/nri3785 · Cited by 3,046 · see citing works
A framework for human microbiome research
The Human Microbiome Project Consortium (2012) · Nature · doi:10.1038/nature11209 · Cited by 2,650 · see citing works
Innate lymphoid cells — a proposal for uniform nomenclature
Spits, H., Artis, D., Colonna, M., Diefenbach, A., Disanto, J. D., Eberl, G., Koyasu, S., Locksley, R., McKenzie, A., Mebius, R., et al. (2013) · Nature reviews. Immunology · doi:10.1038/nri3365 · Cited by 2,380 · see citing works
Occlusal Caries: Biological Approach for Its Diagnosis and Management
Carvalho, J. C., Dige, I., Mačhiulskienė, V., Qvist, V., Bakhshandeh, A., Parolo, C. C. F., & Maltz, M. (2016) · Caries Research · doi:10.1159/000448662 · Cited by 2,159 · see citing works
The IL-23-IL-17 immune axis: from mechanisms to therapeutic testing
Gaffen, S. L., Jain, R., Garg, A. V., & Cua, D. J. (2014) · Nature reviews. Immunology · doi:10.1038/nri3707 · Cited by 1,585 · see citing works
The developmental pathway for CD103+CD8+ tissue-resident memory T cells of skin
Mackay, L. K., Rahimpour, A., Ma, J. Z., Collins, N., Stock, A. T., Hafon, M.-L., Vega-Ramos, J., Lauzurica, P., Mueller, S. N., Stefanovic, T., et al. (2013) · Nature Immunology · doi:10.1038/ni.2744 · Cited by 1,331 · cited 1× · see citing works
“The rTEM cells are thought to be retained in peripheral tissues and not recirculate but become terminally differentiated cells that provide site-specific protection.(36) This dominance of tissue-resident memory cells is similar to other barrier sites such as the lung and small and large intestine.”
Update of the Case Definitions for Population‐Based Surveillance of Periodontitis
Eke, P. I., Page, R. C., Liang, W., Thornton‐Evans, G. O., & Genco, R. J. (2012) · Journal of Periodontology · doi:10.1902/jop.2012.110664 · Cited by 1,328 · see citing works
Pathogenesis of inflammatory periodontal disease. A summary of current work.
Rc, P., & Schroeder, H. E. (1976) · PubMed · Cited by 1,102 · see citing works
Fuchs, A. G., Vermi, W., Lee, J. S., Lonardi, S., Gilfillan, S., Newberry, R. D., Cella, M., & Colonna, M. (2013) · Immunity · doi:10.1016/j.immuni.2013.02.010 · Cited by 904 · see citing works
Skin infection generates non-migratory memory CD8+ TRM cells providing global skin immunity
Jiang, X., Clark, R. A., Liu, L., Wagers, A. J., Fuhlbrigge, R. C., & Kupper, T. S. (2012) · Nature · doi:10.1038/nature10851 · Cited by 883 · see citing works
Chen, C.-J., Kono, H., Golenbock, D., Reed, G., Akira, S., & Rock, K. L. (2007) · Nature Medicine · doi:10.1038/nm1603 · Cited by 876 · see citing works
Distribution and compartmentalization of human circulating and tissue-resident memory T cell subsets
Sathaliyawala, T., Kubota, M., Yudanin, N., Turner, D., Camp, P., Thome, J. J. C., Bickham, K. L., Lerner, H., Goldstein, M., Sykes, M., et al. (2013) · Immunity · doi:10.1016/j.immuni.2012.09.020 · Cited by 848 · see citing works
Dutton, R. W., Bradley, L. M., & Swain, S. L. (1998) · Annual Review of Immunology · doi:10.1146/annurev.immunol.16.1.201 · Cited by 832 · see citing works
Haniffa, M. A., Shin, A., Bigley, V., McGovern, N. N., Teo, P., See, P., Wasan, P. S., Wang, X.-N., Malinarich, F., Malleret, B., et al. (2012) · Immunity · doi:10.1016/j.immuni.2012.04.012 · Cited by 726 · see citing works
Neutrophils: Between Host Defence, Immune Modulation, and Tissue Injury
Krüger, P., Saffarzadeh, M., Weber, A. N. R., Rieber, N. P., Radsak, M. P., von Bernuth, H., Benarafa, C., Roos, D., Skokowa, J., & Hartl, D. (2015) · PLoS Pathogens · doi:10.1371/journal.ppat.1004651 · Cited by 663 · see citing works
Sensing and alarm function of resident memory CD8+ T cells
Schenkel, J., Fraser, K. A., Vezys, V., & Masopust, D. (2013) · Nature Immunology · doi:10.1038/ni.2568 · Cited by 648 · see citing works
Teijaro, J. R., Turner, D., Pham, Q., Wherry, E. J., Lefrançois, L., & Farber, D. L. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1102243 · Cited by 641 · see citing works
Functional Specializations of Human Epidermal Langerhans Cells and CD14+ Dermal Dendritic Cells
Klechevsky, E., Morita, R., Liu, M., Cao, Y., Coquery, S., Thompson-Snipes, L., Brière, F., Chaussabel, D., Zurawski, G., Palucka, K., et al. (2008) · Immunity · doi:10.1016/j.immuni.2008.07.013 · Cited by 618 · see citing works
Bernink, J. H., Krabbendam, L., Germar, K., de Jong, E. C., Gronke, K., Kofoed-Nielsen, M., Munneke, J. M., Hazenberg, M. D., Villaudy, J., Buskens, C. J., et al. (2015) · Immunity · doi:10.1016/j.immuni.2015.06.019 · Cited by 609 · see citing works
Spatial map of human T cell compartmentalization and maintenance over decades of life
Thome, J. J. C., Yudanin, N., Ohmura, Y., Kubota, M., Grinshpun, B., Sathaliyawala, T., Kato, T., Lerner, H., Shen, Y., & Farber, D. L. (2014) · Cell · doi:10.1016/j.cell.2014.10.026 · Cited by 587 · see citing works
The leukocyte integrin antagonist Del-1 inhibits IL-17-mediated inflammatory bone loss
Eskan, M. A., Jotwani, R., Abe, T., Chmelar, J., Lim, J.-H., Liang, S., Ciero, P. A., Krauss, J. L., Li, F., Rauner, M., et al. (2012) · Nature Immunology · doi:10.1038/ni.2260 · Cited by 429 · see citing works
Dynamics of Blood-Borne CD8 Memory T Cell Migration In Vivo
Klonowski, K. D., Williams, K., Marzo, A. L., Blair, D. A., Lingenheld, E. G., & Lefrançois, L. (2004) · Immunity · doi:10.1016/s1074-7613(04)00103-7 · Cited by 383 · see citing works
Compartmentalized and systemic control of tissue immunity by commensals
Belkaid, Y., & Naik, S. (2013) · Nature Immunology · doi:10.1038/ni.2604 · Cited by 382 · see citing works
Hazenberg, M. D., & Spits, H. (2014) · Blood · doi:10.1182/blood-2013-11-427781 · Cited by 376 · see citing works
Heath, W. R., & Carbone, F. (2013) · Nature Immunology · doi:10.1038/ni.2680 · Cited by 356 · see citing works
Memory regulatory T cells reside in human skin
Rodriguez, R. S., Pauli, M. L., Neuhaus, I. M., Yu, S. S., Arron, S. T., Harris, H. W., Yang, S. H.-Y., Anthony, B. A., Sverdrup, F. M., Krow‐Lucal, E., et al. (2014) · Journal of Clinical Investigation · doi:10.1172/jci72932 · Cited by 355 · see citing works
Human dermal CD14(+) cells are a transient population of monocyte-derived macrophages
McGovern, N., Schlitzer, A., Gunawan, M., Jardine, L., Shin, A., Poyner, E., Green, K., Dickinson, R., Wang, X.-N., Low, D., et al. (2014) · Immunity · doi:10.1016/j.immuni.2014.08.006 · Cited by 281 · see citing works
Evidence of the presence of T helper type 17 cells in chronic lesions of human periodontal disease
Cardoso, C. R. D. B., Garlet, G. P., Crippa, G. E., Rosa, A. L., Júnior, W. M., Rossi, M. A., & Silva, J. S. (2008) · Oral Microbiology and Immunology · doi:10.1111/j.1399-302x.2008.00463.x · Cited by 270 · see citing works
Histopathologic features of the initial and early stages of experimental gingivitis in man
Payne, W., Page, R. C., Ogilvie, A., & Hall, W. B. (1975) · Journal of Periodontal Research · doi:10.1111/j.1600-0765.1975.tb00008.x · Cited by 216 · see citing works
Porphyromonas gingivalis promotes Th17 inducing pathways in chronic periodontitis
Moutsopoulos, N. M., Kling, H. M., Angelov, N., Jin, W., Palmer, R. J., Jr., Nares, S., Osorio, M., & Wahl, S. M. (2012) · Journal of Autoimmunity · doi:10.1016/j.jaut.2012.03.003 · Cited by 210 · see citing works
Self-citationJotwani, R., Palucka, A. K., Al-Quotub, M., Nouri-Shirazi, M. A., Kim, J., Bell, D., Banchereau, J., & Cutler, C. W. (2001) · The Journal of Immunology · doi:10.4049/jimmunol.167.8.4693 · Cited by 201 · see citing works
Dynamic visualization of RANKL and Th17-mediated osteoclast function
Kikuta, J., Wada, Y., Kowada, T., Wang, Z., Sun‐Wada, G., Nishiyama, I., Mizukami, S., Maiya, N., Yasuda, H., Kumanogoh, A., et al. (2013) · Journal of Clinical Investigation · doi:10.1172/jci65054 · Cited by 189 · see citing works
Human skin dendritic cells in health and disease
Haniffa, M., Gunawan, M., & Jardine, L. (2015) · Journal of Dermatological Science · doi:10.1016/j.jdermsci.2014.08.012 · Cited by 187 · see citing works
Antibodies to Periodontal Pathogens and Stroke Risk
Pussinen, P. J., Alfthan, G., Rissanen, H. A., et al. (2004) · Stroke · doi:10.1161/01.str.0000136148.29490.fe · Cited by 174 · see citing works
Neutrophil Homeostasis and Periodontal Health in Children and Adults
Hajishengallis, E., & Hajishengallis, G. (2013) · Journal of Dental Research · doi:10.1177/0022034513507956 · Cited by 173 · see citing works
Oral mucosal embryology and histology
Winning, T. A., & Townsend, G. C. (2000) · Clinics in Dermatology · doi:10.1016/s0738-081x(00)00140-1 · Cited by 148 · see citing works
A Three-Dimensional Atlas of Human Dermal Leukocytes, Lymphatics, and Blood Vessels
Wang, X., McGovern, N. N., Gunawan, M., Richardson, C. D., Windebank, M., Siah, T. W., Lim, H. Y., Fink, K., Li, J. L. Y., Ng, L. G., et al. (2013) · Journal of Investigative Dermatology · doi:10.1038/jid.2013.481 · Cited by 140 · see citing works
Immunohistological analysis of experimental gingivitis in humans.
Seymour, G. J., Gemmell, E., Walsh, L. J., & Powell, R. N. (1988) · PubMed Central · Cited by 94 · see citing works
Abe, T., AlSarhan, M., Benakanakere, M. R., Maekawa, T., Kinane, D. F., Cancro, M. P., Korostoff, J. M., & Hajishengallis, G. (2015) · The Journal of Immunology · doi:10.4049/jimmunol.1500496 · Cited by 88 · see citing works
Comparative analysis of nasal and oral mucosa dendritic cells
Allam, J., Niederhagen, B., Bücheler, M., et al. (2005) · Allergy · doi:10.1111/j.1398-9995.2005.00965.x · Cited by 87 · see citing works
Serum Antibodies to Periodontal Bacteria
Gunsolley, J. C., Tew, J. G., Gooss, C. M., et al. (1990) · Journal of Periodontology · doi:10.1902/jop.1990.61.7.412 · Cited by 78 · see citing works
Langerhans cells down-regulate inflammation-driven alveolar bone loss
Arizon, M., Nudel, I., Segev, H., Mizraji, G., Elnekave, M., Furmanov, K., Eli‐Berchoer, L., Clausen, B. E., Shapira, L., Wilensky, A., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1116770109 · Cited by 77 · see citing works
Lappin, D. F., Koulouri, O., Radvar, M., et al. (1999) · Journal Of Clinical Periodontology · doi:10.1034/j.1600-051x.1999.260309.x · Cited by 70 · see citing works
Han, B., Luo, G., Shi, Z.-Z., Barrios, R. J., Atwood, D., Liu, W., Habib, G. M., Sifers, R. N., Corry, D. B., & Lieberman, M. W. (2002) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)64204-6 · Cited by 56 · see citing works
Reduced oxidative function in gingival crevicular neutrophils in periodontal disease
Loesche, W. J., Robinson, J. P., Flynn, M. J., et al. (1988) · Infection and Immunity · doi:10.1128/iai.56.1.156-160.1988 · Cited by 47 · see citing works
Nares, S., Moutsopoulos, N. M., Angelov, N., Rangel, Z. G., Munson, P. J., Sinha, N., & Wahl, S. M. (2009) · American Journal Of Pathology · doi:10.2353/ajpath.2009.080677 · Cited by 36 · see citing works
Self-citationBelkaid, Y., & Artis, D. (2013) · European Journal of Immunology · doi:10.1002/eji.201344133 · Cited by 19 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
The oral microbiome: Role of key organisms and complex networks in oral health and disease
Sedghi, L., DiMassa, V., Harrington, A., Lynch, S. V., & Kapila, Y. L. (2021) · Periodontology 2000 · doi:10.1111/prd.12393 · Cited by 755 · see citing works
Dutzan, N., Kajikawa, T., Abusleme, L., Greenwell-Wild, T., Zuazo, C. E., Ikeuchi, T., Brenchley, L., Abe, T., Hurabielle, C., Martin, D., et al. (2018) · Science Translational Medicine · doi:10.1126/scitranslmed.aat0797 · Cited by 382 · see citing works
Self-citationDutzan, N., Abusleme, L., Bridgeman, H., Greenwell-Wild, T., Zangerle-Murray, T., Fife, M. E., Bouladoux, N., Linley, H., Brenchley, L., Wemyss, K., et al. (2017) · Immunity · doi:10.1016/j.immuni.2016.12.010 · Cited by 252 · see citing works
“C withCollage-naseIV (GIBCO) and DNase (Sigma) as previously described (Dutzan et al., 2016a).”
MethodSelf-citationReview: modulation of the oral microbiome by the host to promote ecological balance
Cornejo Ulloa, P., van der Veen, M. H., & Krom, B. P. (2019) · Odontology · doi:10.1007/s10266-019-00413-x · Cited by 104 · see citing works
Neutrophil Subsets in Periodontal Health and Disease: A Mini Review
Hirschfeld, J. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2019.03001 · Cited by 53 · see citing works
C1R mutations trigger constitutive complement 1 activation in periodontal Ehlers-Danlos syndrome
Gröbner, R., Kapferer-Seebacher, I., Amberger, A., Redolfi, R., Dalonneau, F., Björck, E., Milnes, D., Bally, I., Rossi, V., Thielens, N., et al. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.02537 · Cited by 35 · see citing works
- Authors
- Dutzan, N., Konkel, J. E., Greenwell-Wild, T., & Moutsopoulos, N. M.
- Affiliations
- National Institutes of Health (US)
- University of Manchester (GB)
- Corresponding author
- Moutsopoulos, N.M.
- Venue
- Mucosal Immunology
- Publisher
- Elsevier BV
- Published
- 2016-09
- Volume
- 9
- Issue
- 5
- Pages
- 1163-1172
- ISSN
- 1933-0219 (ISSN-L)
- PMC
- PMC4820049
- OpenAlex
- W2337778730
- Cited by
- 305
- References
- 51
- Citations by year
- 2026: 28 · 2025: 25 · 2024: 29 · 2023: 38 · 2022: 40 · 2021: 51 · 2020: 25 · 2019: 25 · 2018: 24 · 2017: 16 · 2016: 4
- FWCI
- 34.32
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Mucosal Immunology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Research Explorer (The University of Manchester) (submittedVersion)
- Funders
- Wellcome Trust (097820/Z11/B, 105610, 105610/Z/14/Z, 097820, 090207)
- Manchester Collaborative Centre for Inflammation Research
- National Institutes of Health
- Biotechnology and Biological Sciences Research Council (BB/M025977/1)
- National Institute of Dental and Craniofacial Research (ZIADE000736)
- Topics
- Health Sciences › Dentistry › Periodontics › Oral microbiology and periodontitis research
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Dentistry › Periodontics › Oral Health Pathology and Treatment
- Keywords
- oral mucosa, oral immunity, immune cell composition, periodontitis, neutrophils, T cells, B cells, antigen-presenting cells, innate lymphoid cells, IL-17, CD4+ T cells, dental plaque, immune homeostasis, oral microbiota
- MeSH terms
- Antigen-Presenting Cells, B-Lymphocytes, Gene Expression Regulation, Gingiva, Homeostasis, Humans, Immunity, Innate, Leukocyte Count, Mouth Mucosa, Neutrophils, Periodontitis, T-Lymphocytes, Case-Control Studies, Immunophenotyping, Immunity, Mucosal, Interleukin-17
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
