{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T15:32:05Z","timestamp":1761060725185,"version":"3.38.0"},"reference-count":42,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2019,2,1]],"date-time":"2019-02-01T00:00:00Z","timestamp":1548979200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,2,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Contact hypersensitivity (CHS) is a CD8 T cell\u2013mediated response to hapten skin sensitization and challenge. Sensitization of wild-type (WT) mice induces hapten-reactive effector CD8 T cells producing IFN-\u03b3 and IL-17\u2013 and IL-4\u2013producing CD4 T cells that cannot mediate CHS. Although CXCR2-dependent Ly6G+ (neutrophil) cell recruitment into hapten-challenged skin is required to direct effector CD8 T cell infiltration into the challenge site to elicit CHS, 2,4-dinitrofluorobenezene (DNFB) sensitization of CXCR2\u2212\/\u2212 mice and neutrophil-depleted WT mice induced both hapten-reactive CD4 and CD8 T cells producing IFN-\u03b3 and IL-17. CD4 T cell\u2013mediated CHS responses were not generated during DNFB sensitization of neutrophil-depleted WT mice treated with anti\u2013IL-12 mAb or neutrophil-depleted IL-12\u2212\/\u2212 mice. Neutrophil depletion during DNFB sensitization of WT mice markedly increased IL-12\u2013producing hapten-primed dendritic cell numbers in the skin-draining lymph nodes. Sensitization of mice lacking the neutrophil serine protease cathepsin G (CG)\u2013induced hapten-reactive CD4 and CD8 T cells producing IFN-\u03b3 and IL-17 with elevated and elongated CHS responses to DNFB challenge. Induction of CHS effector CD4 T cells producing IFN-\u03b3 in neutrophil-depleted WT mice was eliminated by s.c. injection of active, but not inactivated, CG during sensitization. Thus, hapten skin sensitization induces neutrophil release of CG that systemically inhibits hapten-presenting dendritic cell production of IL-12 and the development of hapten-reactive CD4 T cells to IFN-\u03b3\u2013producing CHS effector cells.<\/jats:p>","DOI":"10.4049\/jimmunol.1800841","type":"journal-article","created":{"date-parts":[[2019,1,7]],"date-time":"2019-01-07T21:10:42Z","timestamp":1546895442000},"page":"1045-1056","source":"Crossref","is-referenced-by-count":11,"title":["Neutrophil Cathepsin G Regulates Dendritic Cell Production of IL-12 during Development of CD4 T Cell Responses to Antigens in the Skin"],"prefix":"10.1093","volume":"202","author":[{"given":"Danielle D","family":"Kish","sequence":"first","affiliation":[{"name":"Lerner Research Institute, Cleveland Clinic , Cleveland, OH 44195"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susie","family":"Min","sequence":"additional","affiliation":[{"name":"Lerner Research Institute, Cleveland Clinic , Cleveland, OH 44195"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nina","family":"Dvorina","sequence":"additional","affiliation":[{"name":"Lerner Research Institute, Cleveland Clinic , Cleveland, OH 44195"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"suffix":"III","given":"William M","family":"Baldwin","sequence":"additional","affiliation":[{"name":"Lerner Research Institute, Cleveland Clinic , Cleveland, OH 44195"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen A","family":"Stohlman","sequence":"additional","affiliation":[{"name":"Lerner Research Institute, Cleveland Clinic , Cleveland, OH 44195"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7107-5259","authenticated-orcid":false,"given":"Robert L","family":"Fairchild","sequence":"additional","affiliation":[{"name":"Lerner Research Institute, Cleveland Clinic , Cleveland, OH 44195"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2019,2,15]]},"reference":[{"key":"2025030417560568600_r1","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1038\/nri3024","article-title":"Neutrophils in the activation and regulation of innate and adaptive immunity","volume":"11","author":"Mantovani","year":"2011","journal-title":"Nat. Rev. Immunol."},{"key":"2025030417560568600_r2","doi-asserted-by":"crossref","first-page":"1283","DOI":"10.1084\/jem.20122220","article-title":"Diverse novel functions of neutrophils in immunity, inflammation, and beyond","volume":"210","author":"M\u00f3csai","year":"2013","journal-title":"J. Exp. Med."},{"key":"2025030417560568600_r3","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1016\/S1357-4310(97)01087-3","article-title":"Allergic contact dermatitis: understanding the immune response and potential for targeted therapy using cytokines","volume":"3","author":"Enk","year":"1997","journal-title":"Mol. Med. Today"},{"key":"2025030417560568600_r4","doi-asserted-by":"crossref","first-page":"1699","DOI":"10.1111\/j.1398-9995.2009.02082.x","article-title":"Effector and regulatory mechanisms in allergic contact dermatitis","volume":"64","author":"Vocanson","year":"2009","journal-title":"Allergy"},{"key":"2025030417560568600_r5","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1007\/s11882-017-0752-8","article-title":"Pathomechanisms of contact sensitization","volume":"17","author":"Esser","year":"2017","journal-title":"Curr. Allergy Asthma Rep."},{"key":"2025030417560568600_r6","doi-asserted-by":"crossref","first-page":"2833","DOI":"10.4049\/jimmunol.145.9.2833","article-title":"Evidence that cutaneous antigen-presenting cells migrate to regional lymph nodes during contact sensitization","volume":"145","author":"Kripke","year":"1990","journal-title":"J. Immunol."},{"key":"2025030417560568600_r7","doi-asserted-by":"crossref","first-page":"1654","DOI":"10.1084\/jem.166.6.1654","article-title":"Localization of antigen on lymph node dendritic cells after exposure to the contact sensitizer fluorescein isothiocyanate. Functional and morphological studies","volume":"166","author":"Macatonia","year":"1987","journal-title":"J. Exp. Med."},{"key":"2025030417560568600_r8","doi-asserted-by":"crossref","first-page":"3530","DOI":"10.4049\/jimmunol.155.7.3530","article-title":"Metabolic requirements for induction of contact hypersensitivity to immunotoxic polyaromatic hydrocarbons","volume":"155","author":"Anderson","year":"1995","journal-title":"J. Immunol."},{"key":"2025030417560568600_r9","doi-asserted-by":"crossref","first-page":"2039","DOI":"10.1172\/JCI117198","article-title":"Processing of urushiol (poison ivy) hapten by both endogenous and exogenous pathways for presentation to T cells in vitro","volume":"93","author":"Kalish","year":"1994","journal-title":"J. Clin. Invest."},{"key":"2025030417560568600_r10","doi-asserted-by":"crossref","first-page":"3006","DOI":"10.1002\/eji.1830251103","article-title":"Major histocompatibility complex class I-restricted CD8+ T cells and class II-restricted CD4+ T cells, respectively, mediate and regulate contact sensitivity to dinitrofluorobenzene","volume":"25","author":"Bour","year":"1995","journal-title":"Eur. J. Immunol."},{"key":"2025030417560568600_r11","doi-asserted-by":"crossref","first-page":"4121","DOI":"10.4049\/jimmunol.144.11.4121","article-title":"Roles of CD4+ and CD8+ T cells in murine contact sensitivity revealed by in vivo monoclonal antibody depletion","volume":"144","author":"Gocinski","year":"1990","journal-title":"J. Immunol."},{"key":"2025030417560568600_r12","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1084\/jem.183.3.1001","article-title":"T cell populations primed by hapten sensitization in contact sensitivity are distinguished by polarized patterns of cytokine production: interferon gamma-producing (Tc1) effector CD8+ T cells and interleukin (Il) 4\/Il-10-producing (Th2) negative regulatory CD4+ T cells","volume":"183","author":"Xu","year":"1996","journal-title":"J. Exp. Med."},{"key":"2025030417560568600_r13","doi-asserted-by":"crossref","first-page":"5949","DOI":"10.4049\/jimmunol.0802830","article-title":"CD8 T cells producing IL-17 and IFN-\u03b3 initiate the innate immune response required for responses to antigen skin challenge","volume":"182","author":"Kish","year":"2009","journal-title":"J. Immunol."},{"key":"2025030417560568600_r14","doi-asserted-by":"crossref","first-page":"2494","DOI":"10.1002\/eji.200636075","article-title":"Activated NKT cells increase dendritic cell migration and enhance CD8+ T cell responses in the skin","volume":"36","author":"Gorbachev","year":"2006","journal-title":"Eur. J. Immunol."},{"key":"2025030417560568600_r15","doi-asserted-by":"crossref","first-page":"156","DOI":"10.4049\/jimmunol.167.1.156","article-title":"IL-12 augments CD8+ T cell development for contact hypersensitivity responses and circumvents anti-CD154 antibody-mediated inhibition","volume":"167","author":"Gorbachev","year":"2001","journal-title":"J. Immunol."},{"key":"2025030417560568600_r16","doi-asserted-by":"crossref","first-page":"3485","DOI":"10.1002\/(SICI)1521-4141(199911)29:11<3485::AID-IMMU3485>3.0.CO;2-B","article-title":"Groalpha-mediated recruitment of neutrophils is required for elicitation of contact hypersensitivity","volume":"29","author":"Dilulio","year":"1999","journal-title":"Eur. J. Immunol."},{"key":"2025030417560568600_r17","doi-asserted-by":"crossref","first-page":"2191","DOI":"10.4049\/jimmunol.1102729","article-title":"Neutrophil expression of Fas ligand and perforin directs effector CD8 T cell infiltration into antigen-challenged skin","volume":"189","author":"Kish","year":"2012","journal-title":"J. Immunol."},{"key":"2025030417560568600_r18","doi-asserted-by":"crossref","first-page":"2443","DOI":"10.4049\/jimmunol.173.4.2443","article-title":"CD40 engagement enhances antigen-presenting langerhans cell priming of IFN-gamma-producing CD4+ and CD8+ T cells independently of IL-12","volume":"173","author":"Gorbachev","year":"2004","journal-title":"J. Immunol."},{"key":"2025030417560568600_r19","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1084\/jem.186.5.739","article-title":"Identification of human neutrophil-derived cathepsin G and azurocidin\/CAP37 as chemoattractants for mononuclear cells and neutrophils","volume":"186","author":"Chertov","year":"1997","journal-title":"J. Exp. Med."},{"key":"2025030417560568600_r20","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1016\/j.immuni.2005.03.015","article-title":"Serine protease cathepsin G regulates adhesion-dependent neutrophil effector functions by modulating integrin clustering","volume":"22","author":"Raptis","year":"2005","journal-title":"Immunity"},{"key":"2025030417560568600_r21","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/S1074-7613(00)80173-9","article-title":"Impaired immunity and enhanced resistance to endotoxin in the absence of neutrophil elastase and cathepsin G","volume":"12","author":"Tkalcevic","year":"2000","journal-title":"Immunity"},{"key":"2025030417560568600_r22","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/j.biochi.2007.10.009","article-title":"Neutrophil elastase, proteinase 3 and cathepsin G: physicochemical properties, activity and physiopathological functions","volume":"90","author":"Korkmaz","year":"2008","journal-title":"Biochimie"},{"key":"2025030417560568600_r23","doi-asserted-by":"crossref","first-page":"3706","DOI":"10.4049\/jimmunol.145.11.3706","article-title":"Enrichment and function of urushiol (poison ivy)-specific T lymphocytes in lesions of allergic contact dermatitis to urushiol","volume":"145","author":"Kalish","year":"1990","journal-title":"J. Immunol."},{"key":"2025030417560568600_r24","doi-asserted-by":"crossref","first-page":"2979","DOI":"10.4049\/jimmunol.167.5.2979","article-title":"Early chemokine cascades in murine cardiac grafts regulate T cell recruitment and progression of acute allograft rejection","volume":"167","author":"Morita","year":"2001","journal-title":"J. Immunol."},{"key":"2025030417560568600_r25","doi-asserted-by":"crossref","first-page":"3728","DOI":"10.4049\/jimmunol.150.9.3728","article-title":"Modulation of in vivo immune response by selective depletion of neutrophils using a monoclonal antibody, RP-3. I. Inhibition by RP-3 treatment of the priming and effector phases of delayed type hypersensitivity to sheep red blood cells in rats","volume":"150","author":"Kudo","year":"1993","journal-title":"J. Immunol."},{"key":"2025030417560568600_r26","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1161\/CIRCULATIONAHA.104.516708","article-title":"Inhibition of polymorphonuclear leukocyte-mediated graft damage synergizes with short-term costimulatory blockade to prevent cardiac allograft rejection","volume":"112","author":"El-Sawy","year":"2005","journal-title":"Circulation"},{"key":"2025030417560568600_r27","doi-asserted-by":"crossref","first-page":"1931","DOI":"10.1172\/JCI118625","article-title":"T lymphocyte recruitment by interleukin-8 (IL-8). IL-8-induced degranulation of neutrophils releases potent chemoattractants for human T lymphocytes both in vitro and in vivo","volume":"97","author":"Taub","year":"1996","journal-title":"J. Clin. Invest."},{"key":"2025030417560568600_r28","doi-asserted-by":"crossref","first-page":"8050","DOI":"10.1128\/JVI.76.16.8050-8057.2002","article-title":"Role for macrophage inflammatory protein 2 (MIP-2), MIP-1alpha, and interleukin-1alpha in the delayed-type hypersensitivity response to viral antigen","volume":"76","author":"Tumpey","year":"2002","journal-title":"J. Virol."},{"key":"2025030417560568600_r29","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1189\/jlb.0304193","article-title":"The intensity of neutrophil infiltration controls the number of antigen-primed CD8 T cells recruited into cutaneous antigen challenge sites","volume":"76","author":"Engeman","year":"2004","journal-title":"J. Leukoc. Biol."},{"key":"2025030417560568600_r30","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1084\/jem.20130062","article-title":"Neutrophils are required for both the sensitization and elicitation phase of contact hypersensitivity","volume":"212","author":"Weber","year":"2015","journal-title":"J. Exp. Med."},{"key":"2025030417560568600_r31","doi-asserted-by":"crossref","first-page":"4035","DOI":"10.4049\/jimmunol.166.6.4035","article-title":"CXC chemokine receptor 2 but not C-C chemokine receptor 1 expression is essential for neutrophil recruitment to the cornea in helminth-mediated keratitis (river blindness)","volume":"166","author":"Hall","year":"2001","journal-title":"J. Immunol."},{"key":"2025030417560568600_r32","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1126\/science.8036519","article-title":"Neutrophil and B cell expansion in mice that lack the murine IL-8 receptor homolog","volume":"265","author":"Cacalano","year":"1994","journal-title":"Science"},{"key":"2025030417560568600_r33","doi-asserted-by":"crossref","first-page":"6503","DOI":"10.4049\/jimmunol.167.11.6503","article-title":"CXCR2 deficiency confers impaired neutrophil recruitment and increased susceptibility during Toxoplasma gondii infection","volume":"167","author":"Del Rio","year":"2001","journal-title":"J. Immunol."},{"key":"2025030417560568600_r34","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1084\/jem.155.3.863","article-title":"Depletion of epidermal langerhans cells and Ia immunogenicity from tape-stripped mouse skin","volume":"155","author":"Streilein","year":"1982","journal-title":"J. Exp. Med."},{"key":"2025030417560568600_r35","doi-asserted-by":"crossref","first-page":"2791","DOI":"10.4049\/jimmunol.145.9.2791","article-title":"Phenotypic and functional characteristics of in vivo-activated Langerhans cells","volume":"145","author":"Aiba","year":"1990","journal-title":"J. Immunol."},{"key":"2025030417560568600_r36","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1093\/intimm\/12.1.103","article-title":"IL-12 is produced by antigen-presenting cells stimulated with soluble alphabeta TCR and restores impaired T(h)1 responses","volume":"12","author":"Kawamoto","year":"2000","journal-title":"Int. Immunol."},{"key":"2025030417560568600_r37","doi-asserted-by":"crossref","first-page":"2151","DOI":"10.1084\/jem.20070509","article-title":"Toll-like receptor and IL-12 signaling control susceptibility to contact hypersensitivity","volume":"205","author":"Martin","year":"2008","journal-title":"J. Exp. Med."},{"key":"2025030417560568600_r38","doi-asserted-by":"crossref","first-page":"6052","DOI":"10.4049\/jimmunol.171.11.6052","article-title":"Cross-talk in the innate immune system: neutrophils instruct recruitment and activation of dendritic cells during microbial infection","volume":"171","author":"Bennouna","year":"2003","journal-title":"J. Immunol."},{"key":"2025030417560568600_r39","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1189\/jlb.0905526","article-title":"Polymorphonuclear neutrophils deliver activation signals and antigenic molecules to dendritic cells: a new link between leukocytes upstream of T lymphocytes","volume":"79","author":"Megiovanni","year":"2006","journal-title":"J. Leukoc. Biol."},{"key":"2025030417560568600_r40","doi-asserted-by":"crossref","first-page":"1281","DOI":"10.1084\/jem.20041276","article-title":"Neutrophils mediate immune modulation of dendritic cells through glycosylation-dependent interactions between Mac-1 and DC-SIGN","volume":"201","author":"van Gisbergen","year":"2005","journal-title":"J. Exp. Med."},{"key":"2025030417560568600_r41","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1002\/eji.200737905","article-title":"Mycobacterium bovis BCG-infected neutrophils and dendritic cells cooperate to induce specific T cell responses in humans and mice","volume":"38","author":"Morel","year":"2008","journal-title":"Eur. J. Immunol."},{"key":"2025030417560568600_r42","doi-asserted-by":"crossref","first-page":"1474","DOI":"10.4049\/jimmunol.1601223","article-title":"Highly selective cleavage of cytokines and chemokines by the human mast cell chymase and neutrophil cathepsin G","volume":"198","author":"Fu","year":"2017","journal-title":"J. Immunol."}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/202\/4\/1045\/61432256\/ji1800841.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/202\/4\/1045\/61432256\/ji1800841.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,4]],"date-time":"2025-03-04T20:08:05Z","timestamp":1741118885000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/202\/4\/1045\/7953570"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,2]]},"references-count":42,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2019,2,15]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.1800841","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"type":"print","value":"0022-1767"},{"type":"electronic","value":"1550-6606"}],"subject":[],"published-other":{"date-parts":[[2019,2]]},"published":{"date-parts":[[2019,2]]}}}