{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T06:04:46Z","timestamp":1789193086972,"version":"build-2803163510"},"reference-count":45,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2021,6,26]],"date-time":"2021-06-26T00:00:00Z","timestamp":1624665600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Whilst the importance of keratinocytes as a first-line defense has been widely investigated, little is known about their interactions with non-resident immune cells. In this study, the impact of human keratinocytes on T cell effector functions was analyzed in an antigen-specific in vitro model of allergic contact dermatitis (ACD) to nickel sulfate. Keratinocytes partially inhibited T cell proliferation and cytokine production. This effect was dependent on the keratinocyte\/T cell ratio and was partially reversible by increasing the number of autologous dendritic cells. The inhibition of T cell proliferation by keratinocytes was independent of the T cell subtype and antigen presentation by different professional antigen-presenting cells. Autologous and heterologous keratinocytes showed comparable effects, while the fixation of keratinocytes with paraformaldehyde abrogated the immunosuppressive effect. The separation of keratinocytes and T cells by a transwell chamber, as well as a cell-free keratinocyte supernatant, inhibited T cell effector functions to the same amount as directly co-cultured keratinocytes, thus proving that soluble factor\/s account for the observed suppressive effects. In conclusion, keratinocytes critically control the threshold of inflammatory processes in the skin by inhibiting T cell proliferation and cytokine production.<\/jats:p>","DOI":"10.3390\/cells10071606","type":"journal-article","created":{"date-parts":[[2021,6,27]],"date-time":"2021-06-27T22:24:57Z","timestamp":1624832697000},"page":"1606","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Keratinocytes Regulate the Threshold of Inflammation by Inhibiting T Cell Effector Functions"],"prefix":"10.3390","volume":"10","author":[{"given":"Peter","family":"Seiringer","sequence":"first","affiliation":[{"name":"Division of Dermatology and Venerology, Department of Medicine Solna and Center for Molecular Medicine, Karolinska Institutet, 17176 Stockholm, Sweden"},{"name":"ZAUM\u2014Center of Allergy and Environment, Technical University and Helmholtz Center Munich, 80802 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1166-2355","authenticated-orcid":false,"given":"Stefanie","family":"Eyerich","sequence":"additional","affiliation":[{"name":"ZAUM\u2014Center of Allergy and Environment, Technical University and Helmholtz Center Munich, 80802 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kilian","family":"Eyerich","sequence":"additional","affiliation":[{"name":"Division of Dermatology and Venerology, Department of Medicine Solna and Center for Molecular Medicine, Karolinska Institutet, 17176 Stockholm, Sweden"},{"name":"ZAUM\u2014Center of Allergy and Environment, Technical University and Helmholtz Center Munich, 80802 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Dittlein","sequence":"additional","affiliation":[{"name":"Chair and Institute of Environmental Medicine, UNIKA-T, Technical University of Munich and Helmholtz Center Munich, 86156 Augsburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Caroline","family":"Pilz","sequence":"additional","affiliation":[{"name":"ZAUM\u2014Center of Allergy and Environment, Technical University and Helmholtz Center Munich, 80802 Munich, Germany"},{"name":"Department of Dermatology and Allergy, Technical University of Munich, 80802 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6848-3262","authenticated-orcid":false,"given":"Emanuele","family":"Scala","sequence":"additional","affiliation":[{"name":"Division of Dermatology and Venerology, Department of Medicine Solna and Center for Molecular Medicine, Karolinska Institutet, 17176 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Ring","sequence":"additional","affiliation":[{"name":"Department of Dermatology and Allergy, Technical University of Munich, 80802 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heidrun","family":"Behrendt","sequence":"additional","affiliation":[{"name":"ZAUM\u2014Center of Allergy and Environment, Technical University and Helmholtz Center Munich, 80802 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Cavani","sequence":"additional","affiliation":[{"name":"Scientific Coordination Unit, National Institute for Health, Migration and Poverty (INMP-NIHMP), 00153 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Traidl-Hoffmann","sequence":"additional","affiliation":[{"name":"Chair and Institute of Environmental Medicine, UNIKA-T, Technical University of Munich and Helmholtz Center Munich, 86156 Augsburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/j.it.2018.02.004","article-title":"Cutaneous Barriers and Skin Immunity: Differentiating A Connected Network","volume":"39","author":"Eyerich","year":"2018","journal-title":"Trends Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e974451","DOI":"10.4161\/21688370.2014.974451","article-title":"Epidermal tight junctions in health and disease","volume":"3","author":"Brandner","year":"2015","journal-title":"Tissue Barriers"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1038\/ni0107-3","article-title":"Organ-specific regulation of innate immunity","volume":"8","author":"Raz","year":"2007","journal-title":"Nat. Immunol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"405","DOI":"10.3389\/fimmu.2019.00405","article-title":"Physiological Regulation of Innate Lymphoid Cells","volume":"10","author":"Jacquelot","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.it.2019.12.004","article-title":"Skin-Resident Innate Lymphoid Cells\u2014Cutaneous Innate Guardians and Regulators","volume":"41","author":"Kobayashi","year":"2020","journal-title":"Trends Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1320","DOI":"10.1016\/j.jaci.2017.07.045","article-title":"Toll-like receptor 7\/8 agonists stimulate plasmacytoid dendritic cells to initiate TH17-deviated acute contact dermatitis in human subjects","volume":"141","author":"Lauffer","year":"2018","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"545","DOI":"10.3390\/ph7050545","article-title":"Human antimicrobial peptides and proteins","volume":"7","author":"Wang","year":"2014","journal-title":"Pharmaceuticals"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1799","DOI":"10.1172\/JCI117528","article-title":"Identification and induction of human keratinocyte-derived IL-12","volume":"94","author":"Muller","year":"1994","journal-title":"J. Clin. Investig."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1146\/annurev.immunol.19.1.423","article-title":"Interleukin-18 regulates both Th1 and Th2 responses","volume":"19","author":"Nakanishi","year":"2001","journal-title":"Annu. Rev. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1007\/s00403-001-0276-9","article-title":"The role of chemokines in allergic contact dermatitis","volume":"293","author":"Sebastiani","year":"2002","journal-title":"Arch. Dermatol. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1046\/j.1523-1747.1998.00098.x","article-title":"Interferon-gamma-stimulated human keratinocytes express the genes necessary for the production of peptide-loaded MHC class II molecules","volume":"110","author":"Albanesi","year":"1998","journal-title":"J. Investig. Dermatol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1729","DOI":"10.1093\/intimm\/dxl107","article-title":"The anti-microbial peptide LL-37 inhibits the activation of dendritic cells by TLR ligands","volume":"18","author":"Kandler","year":"2006","journal-title":"Int. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"5912","DOI":"10.4049\/jimmunol.177.9.5912","article-title":"Impact of bronchial epithelium on dendritic cell migration and function: Modulation by the bacterial motif KpOmpA","volume":"177","author":"Pichavant","year":"2006","journal-title":"J. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1038\/90667","article-title":"Pulmonary dendritic cells producing IL-10 mediate tolerance induced by respiratory exposure to antigen","volume":"2","author":"Akbari","year":"2001","journal-title":"Nat. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1689","DOI":"10.1002\/eji.200737936","article-title":"Airway epithelial cells modify immune responses by inducing an anti-inflammatory microenvironment","volume":"38","author":"Mayer","year":"2008","journal-title":"Eur. J. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"455","DOI":"10.3389\/fimmu.2018.00455","article-title":"Induction of Interleukin-10 Producing Dendritic Cells As a Tool to Suppress Allergen-Specific T Helper 2 Responses","volume":"9","author":"Schulke","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Phan, T.S., Schink, L., Mann, J., Merk, V.M., Zwicky, P., Mundt, S., Simon, D., Kulms, D., Abraham, S., and Legler, D.F. (2021). Keratinocytes control skin immune homeostasis through de novo-synthesized glucocorticoids. Sci. Adv., 7.","DOI":"10.1126\/sciadv.abe0337"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"7032","DOI":"10.3892\/mmr.2017.7492","article-title":"A novel noncontact communication between human keratinocytes and T cells: Exosomes derived from keratinocytes support superantigeninduced proliferation of resting T cells","volume":"16","author":"Cai","year":"2017","journal-title":"Mol. Med. Rep."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1186\/s13287-020-01929-8","article-title":"Shedding light on the role of keratinocyte-derived extracellular vesicles on skin-homing cells","volume":"11","author":"Nasiri","year":"2020","journal-title":"Stem Cell Res. Ther."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1038\/s41423-019-0261-x","article-title":"Keratinocytes costimulate naive human T cells via CD2: A potential target to prevent the development of proinflammatory Th1 cells in the skin","volume":"17","author":"Orlik","year":"2020","journal-title":"Cell. Mol. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1111\/cod.13119","article-title":"Prevalence of contact allergy in the general population: A systematic review and meta-analysis","volume":"80","author":"Alinaghi","year":"2019","journal-title":"Contact Dermat."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1111\/cod.13327","article-title":"Nickel allergy and allergic contact dermatitis: A clinical review of immunology, epidemiology, exposure, and treatment","volume":"81","author":"Ahlstrom","year":"2019","journal-title":"Contact Dermat."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3058","DOI":"10.4049\/jimmunol.165.6.3058","article-title":"Disparate cytotoxic activity of nickel-specific CD8+ and CD4+ T cell subsets against keratinocytes","volume":"165","author":"Traidl","year":"2000","journal-title":"J. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1023\/A:1009620329213","article-title":"Role of dysregulated apoptosis in atopic dermatitis","volume":"5","author":"Trautmann","year":"2000","journal-title":"Apoptosis"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1016\/0091-6749(92)90434-4","article-title":"House dust mite-specific T cells in the skin of subjects with atopic dermatitis: Frequency and lymphokine profile in the allergen patch test","volume":"89","author":"Sager","year":"1992","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"996","DOI":"10.4049\/jimmunol.166.2.996","article-title":"Chemokine receptor expression and function in CD4+ T lymphocytes with regulatory activity","volume":"166","author":"Sebastiani","year":"2001","journal-title":"J. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1084\/jem.179.4.1109","article-title":"Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte\/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor alpha","volume":"179","author":"Sallusto","year":"1994","journal-title":"J. Exp. Med."},{"key":"ref_28","first-page":"189","article-title":"Topological proteomics, toponomics, MELK-technology","volume":"83","author":"Schubert","year":"2003","journal-title":"Adv. Biochem. Eng. Biotechnol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1270","DOI":"10.1038\/nbt1250","article-title":"Analyzing proteome topology and function by automated multidimensional fluorescence microscopy","volume":"24","author":"Schubert","year":"2006","journal-title":"Nat. Biotechnol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1046\/j.0022-202x.2001.01574.x","article-title":"Activation of nickel-specific CD4+ T lymphocytes in the absence of professional antigen-presenting cells","volume":"118","author":"Nasorri","year":"2002","journal-title":"J. Investig. Dermatol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1172\/JCI10438","article-title":"No eczema without keratinocyte death","volume":"106","author":"Schwarz","year":"2000","journal-title":"J. Clin. Investig."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1038\/jid.2013.417","article-title":"Crosstalk between keratinocytes and T cells in a 3D microenvironment: A model to study inflammatory skin diseases","volume":"134","author":"Tjabringa","year":"2014","journal-title":"J. Investig. Dermatol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1038\/labinvest.2012.69","article-title":"Pathological crosstalk in vitro between T lymphocytes and lesional keratinocytes in psoriasis: Necessity of direct cell-to-cell contact","volume":"92","author":"Martin","year":"2012","journal-title":"Lab. Investig."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2216","DOI":"10.4049\/jimmunol.141.7.2216","article-title":"Class II MHC-bearing keratinocytes induce antigen-specific unresponsiveness in hapten-specific Th1 clones","volume":"141","author":"Gaspari","year":"1988","journal-title":"J. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"4155","DOI":"10.4049\/jimmunol.147.12.4155","article-title":"Induction of in vivo hyporesponsiveness to contact allergens by hapten-modified Ia+ keratinocytes","volume":"147","author":"Gaspari","year":"1991","journal-title":"J. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1159\/000109290","article-title":"Pollen Grains Induce a Rapid and Biphasic Eczematous Immune Response in Atopic Eczema Patients","volume":"145","author":"Eyerich","year":"2007","journal-title":"Int. Arch. Allergy Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"107","DOI":"10.2147\/COPD.S235054","article-title":"How Do Innate Immune Cells Contribute to Airway Remodeling in COPD Progression?","volume":"15","author":"Bu","year":"2020","journal-title":"Int. J. Chronic Obstr. Pulm. Dis."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1038\/s41385-019-0158-0","article-title":"Regulatory cytokine function in the respiratory tract","volume":"12","author":"Branchett","year":"2019","journal-title":"Mucosal Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1016\/j.jdermsci.2019.04.008","article-title":"Keratinocyte-derived TGFbeta is not required to maintain skin immune homeostasis","volume":"94","author":"Yang","year":"2019","journal-title":"J. Dermatol. Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1002\/(SICI)1097-4652(200003)182:3<311::AID-JCP1>3.0.CO;2-9","article-title":"The Ki-67 protein: From the known and the unknown","volume":"182","author":"Scholzen","year":"2000","journal-title":"J. Cell. Physiol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1038\/nri2115","article-title":"Life and death in peripheral T cells","volume":"7","author":"Krammer","year":"2007","journal-title":"Nat. Rev. Immunol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"5760","DOI":"10.4049\/jimmunol.171.11.5760","article-title":"Human CD25+ regulatory T cells maintain immune tolerance to nickel in healthy, nonallergic individuals","volume":"171","author":"Cavani","year":"2003","journal-title":"J. Immunol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1016\/j.jaci.2005.10.040","article-title":"Absence of T-regulatory cell expression and function in atopic dermatitis skin","volume":"117","author":"Verhagen","year":"2006","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Martin, S.F., Rustemeyer, T., and Thyssen, J.P. (2018). Recent advances in understanding and managing contact dermatitis. F1000Research, 7.","DOI":"10.12688\/f1000research.13499.1"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1111\/j.0022-202X.2004.22409.x","article-title":"Expression of indoleamine 2,3-dioxygenase in dermal fibroblasts functions as a local immunosuppressive factor","volume":"122","author":"Ghahary","year":"2004","journal-title":"J. Investig. Dermatol."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/7\/1606\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:24:54Z","timestamp":1760163894000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/7\/1606"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,26]]},"references-count":45,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2021,7]]}},"alternative-id":["cells10071606"],"URL":"https:\/\/doi.org\/10.3390\/cells10071606","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,26]]}}}