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Infiltration Into Antigen-Challenged Skin Perforin Directs Effector CD8 T

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Infiltration Into Antigen-Challenged Skin Perforin Directs Effector CD8 T Neutrophil Expression of Fas Ligand and Perforin Directs Effector CD8 T Cell Infiltration into Antigen-Challenged Skin This information is current as Danielle D. Kish, Anton V. Gorbachev, Neetha of September 26, 2021. Parameswaran, Neetu Gupta and Robert L. Fairchild J Immunol 2012; 189:2191-2202; Prepublished online 18 July 2012; doi: 10.4049/jimmunol.1102729 http://www.jimmunol.org/content/189/5/2191 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2012/07/18/jimmunol.110272 Material 9.DC1 http://www.jimmunol.org/ References This article cites 49 articles, 24 of which you can access for free at: http://www.jimmunol.org/content/189/5/2191.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 26, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2012 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Neutrophil Expression of Fas Ligand and Perforin Directs Effector CD8 T Cell Infiltration into Antigen-Challenged Skin Danielle D. Kish,* Anton V. Gorbachev,* Neetha Parameswaran,* Neetu Gupta,*,† and Robert L. Fairchild*,† Contact hypersensitivity (CHS) is a T cell response to hapten skin challenge of sensitized individuals proposed to be mediated by hapten-primed CD8 cytolytic T cells. Effector CD8 T cell recruitment into hapten challenge sites to elicit CHS requires prior CXCL1- and CXCL2-mediated neutrophil infiltration into the site. We investigated whether neutrophil activities directing hapten-primed CD8 T cell skin infiltration in response to 2,4-dinitro-1-fluorobenzene (DNFB) required Fas ligand (FasL) and per- forin expression. Although DNFB sensitization of gld/perforin2/2 mice induced hapten-specific CD8 T cells producing IFN-g and IL-17, these T cells did not infiltrate the DNFB challenge site to elicit CHS but did infiltrate the challenge site and elicit CHS when transferred to hapten-challenged naive wild-type recipients. Hapten-primed wild-type CD8 T cells, however, did not elicit CHS Downloaded from when transferred to naive gld/perforin2/2 recipients. Wild-type bone marrow neutrophils expressed FasL and perforin, and when transferred to sensitized gld/perforin2/2 mice, they restored hapten-primed CD8 T cell infiltration into the challenge site and CHS. The FasL/perforin-mediated activity of wild-type neutrophils induced the expression of T cell chemoattractants, CCL1, CCL2, and CCL5, within the hapten-challenged skin. These results indicate FasL/perforin-independent functions of hapten- primed CD8 T cells in CHS and identify new functions for neutrophils in regulating effector CD8 T cell recruitment and immune responses in the skin. The Journal of Immunology, 2012, 189: 2191–2202. http://www.jimmunol.org/ ffector CD8 T cells are critical components of immune recruitment of these CD8 T cell populations into the skin challenge responses against intracellular pathogens and tumors. site and their activation to mediate the characteristic edema of the E Following Ag priming in peripheral lymphoid organs, the response. The factors directing the CD8 T cells through the vascular effector CD8 T cells must traffic to the tissue site of the inflam- endothelial barrier and into the skin parenchymal tissue of the matory insult to elicit the response. Current paradigms propose challenge site remain poorly defined. Our previous studies have that integrins and chemokines function synergistically to direct indicated that skin challenge of hapten-sensitized mice is quickly Ag-primed CD8 T cell arrest in the vasculature of inflammatory followed by the recruitment of the hapten-primed CD8 T cells to the sites and into parenchymal tissues during the elicitation of immune vasculature of the challenge site where they are activated to produce by guest on September 26, 2021 responses (1). Additional factors required to induce the chemo- IL-17 and IFN-g by endothelial cells presenting the challenge attractants directing the infiltration of CD8 T cells into paren- hapten (10, 12). These cytokines stimulate the endothelial cells to chymal tissues during elicitation of immune responses remain produce the neutrophil chemoattractants CXCL1 and CXCL2, incompletely identified. which direct the neutrophils into the skin parenchyma. The sub- The most frequently observed dermatosis in industrialized sequent infiltration of the hapten-primed CD8 T cells into the skin countries is allergic contact dermatitis, or contact hypersensitivity parenchymal tissue of the hapten challenge site and the CHS re- (CHS), a T cell-mediated immune response to epidermal sensiti- sponse are inhibited when hapten-sensitized mice are given either zation and subsequent challenge with the sensitizing hapten (2–5). CXCL1- and CXCL2-neutralizing Abs or neutrophil-depleting Abs Hapten-specific CD8 T cell populations producing IFN-g and IL-17 at the time of hapten challenge (13, 14), indicating that prior are primed during skin sensitization and are the primary effector CXCL1/CXCL2-directed neutrophil infiltration and activation di- T cells mediating CHS responses to 2,4-dinitro-1-fluorobenzene rect the subsequent infiltration of the hapten-primed CD8 T cells (DNFB), oxazolone, and urushiol, the reactive hapten of poison into the skin parenchymal tissue during elicitation of CHS. The ivy (6–11). Hapten challenge of sensitized individuals induces the neutrophil functions directing this CD8 T cell infiltration during the elicitation of CHS have remained unknown. Because CD8 T cells are the major effector T cells in CHS *Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, responses, there has been considerable interest in the possibility † OH 44195; and Department of Pathology, Case Western Reserve University School that these T cells express cytolytic functions to elicit the response. of Medicine, Cleveland, OH 44106 One group of investigators has reported the absence of CHS Received for publication September 21, 2011. Accepted for publication June 23, 2/2 2012. responses following sensitization and challenge of gld/perforin This work was supported by National Institutes of Allergy and Infectious Diseases mice, whereas mice with the single Fas ligand (FasL) or perforin Grant R01 AI45888. deficiency had normal CHS responses (15). These observations led Address correspondence and reprint requests to Dr. Robert L. Fairchild, Cleveland to the proposal that CD8 T cells must express cytolytic activity Clinic, Lerner Research Institute, 9500 Euclid Avenue, NB3-59, Cleveland, OH through either the FasL or perforin/granzyme B pathway within 44195-0001. E-mail address: [email protected] the hapten challenge site to mediate CHS responses. Observations The online version of this article contains supplemental material. of keratinocyte apoptosis during the elicitation of CHS were Abbreviations used in this article: CHS, contact hypersensitivity; DNFB, 2,4-dinitro- consistent with this proposal (16). However, examination of 1-fluorobenzene; FasL, Fas ligand; qRT-PCR, quantitative RT-PCR. hapten-primed CD8 T cells has failed to demonstrate expression Copyright Ó 2012 by The American Association of Immunologists, Inc. 0022-1767/12/$16.00 of FasL, and the primed CD8 T cells do not exhibit cytolytic www.jimmunol.org/cgi/doi/10.4049/jimmunol.1102729 2192 NEUTROPHIL MEDIATORS DIRECTING T CELLS INTO SKIN functions when cocultured with hapten-labeled targets, raising the Quantitation of CXCL1 and CXCL2 in skin by immunoassay possibility that the requirement for either FasL or perforin is CXCL1 and CXCL2 levels in skin were determined by ELISA. Mice were mediated through expression by other cells participating in the sensitized by application of 10 ml 0.25% DNFB to each side of each ear on elicitation of CHS responses (17–19). In this study, we investi- days 0 and +1. On day +5 the shaved trunk skin of both sensitized and gated mechanisms underlying the absent CHS responses following nonsensitized mice was challenged with 25 ml DNFB and the challenged challenge of hapten-sensitized gld/perforin2/2 mice. The results skin was excised 6 h later and homogenized in 500 ml proteinase inhibitor mixture (Sigma-Aldrich) with gentle shaking for 30 min. Following cen- indicate a novel function for neutrophils in expressing both FasL trifugation at 12,000 3 g for 10 min, supernatants were collected and total and perforin, which induce T cell chemoattractants and promote protein concentrations quantified using a Coomassie Plus protein assay CD8 T cell infiltration into the skin to mediate CHS. reagent kit (Pierce, Rockford, IL). All samples were diluted to an equiv- alent total protein concentration and tested in CXCL1- and CXCL2- Materials and Methods specific ELISA. Mice Analysis of tissue-infiltrating cells by flow cytometry C57BL/6 (H-2b) mice were obtained through Dr. Clarence Reeder (Na- The shaved trunk skin of sensitized and nonsensitized wild-type and gld/ tional Cancer Institute, Frederick, MD) and gld and perforin2/2 mice on perforin2/2 mice was challenged with DNFB and 6 or 18 h later the chal- a C57BL/6 background were obtained from The Jackson Laboratory (Bar lenged skin was removed and incubated in 0.5% dispase (Invitrogen Life Harbor, ME). Perforin2/2 and gld mice were first crossed to produce gld+/2/ Technologies, Carlsbad, CA) at 4˚C for 18 h. In some experiments groups of perforin+/2 mice and then these were intercrossed and the gld/perforin2/2 sensitized gld/perforin2/2 mice and anti–Gr-1 mAb-treated wild-type mice mice identified through PCR analysis of isolated tissue DNA.
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