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A Novel Inhibitory Cytokine of NK Cell Function

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A Novel Inhibitory Cytokine of NK Cell Function Dendritic Cell−Derived IL-32α: A Novel Inhibitory Cytokine of NK Cell Function Laurent Gorvel, Daniel Korenfeld, Thomas Tung and Eynav Klechevsky This information is current as of September 27, 2021. J Immunol published online 12 July 2017 http://www.jimmunol.org/content/early/2017/07/12/jimmun ol.1601477 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2017/07/12/jimmunol.160147 Material 7.DCSupplemental Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 27, 2021 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 Author Choice Freely available online through The Journal of Immunology Author Choice option 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 © 2017 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published July 12, 2017, doi:10.4049/jimmunol.1601477 The Journal of Immunology Dendritic Cell–Derived IL-32a: A Novel Inhibitory Cytokine of NK Cell Function Laurent Gorvel,* Daniel Korenfeld,* Thomas Tung,† and Eynav Klechevsky* Cytokines produced by dendritic cells (DCs) can largely determine the direction of immunity. Transcriptional analysis revealed that besides IL-15, IL-32 was the only other cytokine expressed by human Langerhans cells. IL-32 is a human cytokine that exists in four main isoforms. Currently, little is known about the regulation and function of the various IL-32 isoforms. In this study, we found that IL-15 is a potent inducer of IL-32a in DCs. Because IL-15 promotes NK cell activation, we investigated the interplay between IL-32 and IL-15 and their role in NK cell activity. We show that IL-32a acts on NK cells to inhibit IL-15–mediated STAT5 phosphor- ylation and to suppress their IL-15–induced effector molecule expression and cytolytic capacity. IL-32a also acted on DCs by downregulating IL-15–induced IL-18 production, an important cytokine in NK cell activity. Blocking IL-32a during DC:NK cell coculture enhanced NK cell effector molecule expression as well as their cytolytic capacity. Taken together, our findings suggest a Downloaded from feedback inhibition of IL-15–mediated NK cell activity by IL-32a. The Journal of Immunology, 2017, 199: 000–000. endritic cells (DCs) are professional APCs that upon CD14+ DCs, is important for the priming of naive B cells into activation are able to migrate to lymphoid organs and IgM-secreting plasma cells (10) and for the generation of follic- D shape immune responses (1). DCs are known to induce a ular Th cells (11). wide range of T cell responses, including Th1, Th2, Th22, Th17, In addition to directing lymphocytes, DCs provide positive and http://www.jimmunol.org/ and CTL responses (2, 3). Specific DC subtypes are specialized at negative signals that are important for priming NK cell responses inducing specific T cell responses. To achieve this, they use a (12–16). For example, fractalkine promotes NK activation by DCs unique set of costimulatory molecules and secrete specific cyto- (17), IL-15 is important for the induction of effector molecules kines (4). In human skin, four different DC subsets have been (18, 19), whereas IL-12, IL-18, and TNF-a are important for IFN-g described: Langerhans cells (LCs) that reside in the epidermis and production by NK cells (20–22). three dermal DC populations that express either CD1a at an in- IL-32 (NK-4), which was initially cloned from human NK cells termediate level (CD1adim) or CD14. The CD1adim population is (23), is a recently identified human cytokine that exists in four heterogeneous and contains CD141-expressing DCs (4). Each one main isoforms: a, b, g, and d (23). Each isoform of IL-32 seems of these subsets produces unique cytokines, which contribute to to possess a different immune function. IL-32g has been described by guest on September 27, 2021 their ability to drive a specific T cell response. For instance, LCs to induce proinflammatory responses by promoting IL-1b, TNF-a, produce IL-15, which supports their ability to prime CTL re- or IL-18 expression (24). However, IL-32a isoform inhibits the sponses (4, 5). IL-15 was also shown to be important for Th17 expression of IL-6 and TNF-a (25). IL-32 has been described in induction by LCs (6, 7). Alternatively, IL-10 was shown to play a various diseases, including atopic dermatitis (26), Helicobacter role in the induction of regulation of T cell responses by dermal pylori gastric inflammation (27), HIV infection (28), and esoph- CD14+ DCs (8, 9). IL-12, which is also produced by dermal ageal cancer (29), and was correlated with either a good or bad prognosis. The preferential expression of a specific IL-32 isoform in these different diseases may help explain its role in pathogen- *Division of Immunobiology, Department of Pathology and Immunology, Washing- † esis. Very few studies have described the induction and regulation ton University School of Medicine, St. Louis, MO 63110; and Division of Plastic and Reconstructive Surgery, Department of Surgery, Washington University School of IL-32 expression and its biological significance. Particularly, of Medicine, St. Louis, MO 63110 there have been limited studies on the roles of each specific iso- ORCID: 0000-0001-7526-261X (L.G.). form. One important study links IL-32 to IL-15–induced defense Received for publication August 24, 2016. Accepted for publication June 11, 2017. response against Mycobacterium tuberculosis in macrophages dim This work was supported by a grant from the Siteman Cancer Center and funding (30). Interestingly, we found that skin LCs and dermal CD1a from the Department of Pathology and Immunology, Washington University School CD1412 DCs express IL-15 and IL-32. In this work, we examine of Medicine (to E.K.). the interplay between IL-15 and IL-32, and its impact on DC and L.G. designed and performed experiments, analyzed data, prepared figures, and wrote NK cell function. the manuscript; D.K. contributed essential technical assistance, performed experi- ments, and wrote the manuscript; T.T. provided access to skin samples; and E.K. conceived, designed, and supervised the study, acquired funding, and wrote the manuscript. Materials and Methods Address correspondence and reprint requests to Dr. Eynav Klechevsky, Department DC subsets of Pathology and Immunology, Washington University School of Medicine, 425 S. Euclid Avenue, St. Louis, MO 63110. E-mail address: [email protected] Human skin specimens were obtained from donors who underwent cosmetic and plastic surgeries at Washington University School of Medicine and The online version of this article contains supplemental material. Barnes Jewish Hospital (St. Louis, MO) in accordance with Institutional 2 Abbreviations used in this article: Ct, cycle threshold; DC, dendritic cell; FC, fold Review Board guidelines. LCs, dermal CD1adimCD141 , CD1adimCD141+ change; LC, Langerhans cell; moDC, monocyte-derived DC. DCs, and CD14+ DCs were purified from normal human skin, as previ- This article is distributed under The American Association of Immunologists, Inc., ously described (31). In brief, specimens were incubated with the bacterial Reuse Terms and Conditions for Author Choice articles. protease dispase type II for 18 h at 4˚C. Epidermal and dermal layers were separated and placed in RPMI 1640 supplemented with 10% FBS. After Copyright Ó 2017 by The American Association of Immunologists, Inc. 0022-1767/17/$30.00 48 h, the cells that migrated into the medium were enriched using a Ficoll www.jimmunol.org/cgi/doi/10.4049/jimmunol.1601477 2 IL-32 IS AN ANTIDOTE FOR IL-15 gradient. DCs were purified by cell sorting after staining with HLA-DR Real-time quantitative RT-PCR (G46.6; BD Biosciences), CD1a (NA1/34; Dako), CD141 (AD14H12; Miltenyi Biotec), and CD14 (Tuk4;€ Thermo Fisher) mAbs. mRNA expression of IL-32 isoforms was assessed by quantitative RT-PCR To obtain monocyte-derived DCs (moDCs), CD14+ monocytes were using SYBR Green Fast Master Mix (Roche Diagnostics) using ABI7900 isolated from PBMCs using microbeads (Miltenyi Biotec) or by adherence Fast Real-Time PCR System (Thermo Fisher). In brief, 50 ng RNAwas used and incubated for 3 d in RPMI 1640 containing 10% FBS and 100 ng/ml per reaction to generate cDNA using oligo(dT) primers and Superscript III GM-CSF (Leukine; Senofi). To generate IFN-a moDCs or IL-15 moDCs, transcriptase (Thermo Fisher). IL-32 isoform expression was detected using 500 U/ml IFN-a (Schering) or 200 ng/ml IL-15 (R&D Systems) was added the following specific primers: IL-32a forward, 59-GCT GGA GGA CGA to the culture, respectively (32). To obtain IL-32a moDCs, 100 ng/ml CTT CAA AGA-39 and reverse, 59-CAG TGG AGC TGG GTC ATC TCA- IL-32a (R&D Systems) was added to the culture. Cytokines were replen- 39; IL-32b forward, 59-CAG TGG AGC TGG GTC ATC TCA-39 and ished on day 1; cells were harvested on day 3. reverse, 59-GGG CCT TCA GCT TCT TCA TGT CAT CA-39; IL-32g forward, 59-CCA CAG TGT CCT CAG TGT CAC A-39 and reverse, 59- NK cell isolation AGG CCC GAA TGG TAA TGC T-39; and IL-32d forward, 59-GCC TTG GCT CCT TGA ACT TTT G-39 and reverse, 59-TTT GAA GTC GTC Blood from healthy donors was provided by the Pheresis Center of Barnes CTG TCC ACG T-39.
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