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Herpes Simplex Virus Antigens Directly Activate NK Cells Via TLR2

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Herpes Simplex Virus Antigens Directly Activate NK Cells Via TLR2 Herpes Simplex Virus Antigens Directly Activate NK Cells via TLR2, Thus Facilitating Their Presentation to CD4 T Lymphocytes This information is current as of September 27, 2021. Min Kim, Naomi R. Osborne, Weiguang Zeng, Heather Donaghy, Kay McKinnon, David C. Jackson and Anthony L. Cunningham J Immunol 2012; 188:4158-4170; Prepublished online 30 March 2012; Downloaded from doi: 10.4049/jimmunol.1103450 http://www.jimmunol.org/content/188/9/4158 http://www.jimmunol.org/ References This article cites 80 articles, 42 of which you can access for free at: http://www.jimmunol.org/content/188/9/4158.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 27, 2021 • 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 Herpes Simplex Virus Antigens Directly Activate NK Cells via TLR2, Thus Facilitating Their Presentation to CD4 T Lymphocytes Min Kim,*,† Naomi R. Osborne,*,† Weiguang Zeng,‡ Heather Donaghy,* Kay McKinnon,x David C. Jackson,‡ and Anthony L. Cunningham*,† NK cells infiltrate human herpetic lesions, but their role has been underexplored. HSV can stimulate innate immune responses via surface TLR2, which is expressed on monocyte-derived dendritic cells (DCs) and NK cells. In this study, UV-inactivated HSV1/2 and immunodominant HSV2 glycoprotein D peptides conjugated to the TLR2 agonist dipalmitoyl-S-glyceryl cysteine stimulated CD4 T lymphocyte IFN-g responses within PBMCs or in coculture with monocyte-derived DCs. NK cells contributed markedly to the PBMC responses. Furthermore, NK cells alone were activated directly by both Ags, also upregulating HLA-DR and HLA-DQ Downloaded from and then they activated autologous CD4 T lymphocytes. Using Transwells, Ag-stimulated NK cells and CD4 T lymphocytes were shown to interact through both cell-to-cell contact and cytokines, differing in relative importance in different donors. A distinct immunological synapse between Ag-stimulated NK cells and CD4 T lymphocytes was observed, indicating the significance of their cell-to-cell contact. A large proportion (57%) of NK cells was also in contact with CD4 T lymphocytes in the dermal infiltrate of human recurrent herpetic lesions. Thus, NK cells stimulated by TLR2-activating HSV Ags can present Ag alone or augment the role of DCs in vitro and perhaps in herpetic lesions or draining lymph nodes. In addition to DCs, NK cells should be considered as http://www.jimmunol.org/ targets for adjuvants during HSV vaccine development. The Journal of Immunology, 2012, 188: 4158–4170. n cutaneous herpes simplex lesions of humans and in mu- MHC class I expression by keratinocytes. This is reversed by rine models, keratinocytes, dendritic cells (DCs), and infil- IFN-g, mainly from early infiltrating CD4 T lymphocytes, thus I trating lymphocytes, especially HSV-specific CD4 and CD8 allowing CD8 T lymphocytes to recognize infected keratinocytes T lymphocytes, were shown to play a central role in control- (1, 4). IFN-g also stimulates MHC class II (MHC II) expression on ling primary and recurrent HSV infections (1). In human recur- keratinocytes, allowing recognition by CD4 T lymphocytes. Thus, rent lesions, monocytes and CD4 T lymphocytes infiltrate first, Th1, rather than Th2, patterns of response are important for im- followed by CD8 T lymphocytes, which appear to clear HSV in- mune and vaccine control of HSV (6). Furthermore, resident by guest on September 27, 2021 fection (1–3). HSV infection of keratinocytes in vitro and in vivo memory CD8 T lymphocytes can be induced to proliferate directly induces the secretion of a sequence of chemokines and cytokines in (murine) skin without the requirement to migrate to the lymph (first IFN-b and b chemokines and then IL-12, followed by IL-1b nodes. This requires DC interactions with CD4 and CD8 T lym- and IL-6) (4). The b chemokines probably attract monocytes and phocytes (7). Infrequent “sentinel” CD4 and CD8 T lympho- CD4 and CD8 T lymphocytes into lesions. IFN-a/b and IL-12 cytes are present in the dermis between lesions. Residual dermal may entrain Th1 patterns of cytokine response from HSV Ag- DCs, plasmacytoid DCs (pDCs), and CD4 and CD8 T lympho- stimulated CD4 (and CD8) T lymphocytes, especially IFN-g. cytes persist in the dermis between lesions. CD8 T lymphocytes IFN-a and IFN-g synergize to inhibit infection of keratinocytes are most superficial, with some present at the dermo–epidermal after transmission from axon termini (5). HSV1/2 downregulate junction (8). Mucocutaneous HSV infection is usually confined to the epi- dermal layer. Therefore, Langerhans cells (LCs) are likely to be *Centre for Virus Research, Westmead Millennium Institute, Westmead, New South involved in initial HSV Ag uptake (9), as shown by older murine Wales 2145, Australia; †Sydney Medical School, University of Sydney, Sydney, New ‡ studies (10). However, recent studies in mice demonstrated that South Wales 2006, Australia; Department of Microbiology and Immunology, Uni- + versity of Melbourne, Parkville, Victoria 3010, Australia; and xParramatta Sexual migrating dermal CD103 , langerin-expressing DCs are the major Health Clinic, Parramatta, New South Wales 2150, Australia transporters of HSVAg out of skin and, together with resident CD8+ Received for publication December 9, 2011. Accepted for publication February 16, DCs, are the major presenters of HSVAg to CD8 T lymphocytes in 2012. lymph nodes (11, 12), probably after Ag transfer from LCs (13). No This work was supported by the National Health and Medical Research Council of human equivalent of the CD103+ dermal DC subset has been de- Australia (Program Grant 358399 and Project Grant 632638). scribed, nor has a similar sequence of events, although it was shown Address correspondence and reprint requests to Prof. Anthony L. Cunningham, West- mead Millennium Institute, Darcy Road, Westmead, NSW 2145, Australia. E-mail that HSV-infected monocyte-derived DCs (MDDCs) undergo apo- address: [email protected] ptosis and can be taken up by bystander uninfected MDDCs, which Abbreviations used in this article: DC, dendritic cell; gD, HSV glycoprotein D; gD2, can then present HSV Ag to CD8 T lymphocytes (14). HSV2 glycoprotein D; gD2-24-4, HSV2 glycoprotein D peptide 24-4; gD2-30-5, More recently, the important role of other innate immune ef- HSV2 glycoprotein D peptide 30-5; hTLR2, human TLR2; IS, immunological syn- apse; LC, Langerhans cell; MDDC, monocyte-derived dendritic cell; MHC II, MHC fectors, both humoral and cellular, such as macrophages, pDCs, class II; MOI, multiplicity of infection; Pam2Cys, dipalmitoyl-S-glyceryl cysteine; NK cells, and gd T lymphocytes has been re-emphasized, either in pDC, plasmacytoid dendritic cell; RH10, RPMI 1640 supplemented with 10% human direct immune control or via modulation of adaptive immune AB serum; RT, room temperature; UV-HSV, UV-inactivated HSV. responses (15, 16). Recently, pDCs were demonstrated to infiltrate Copyright Ó 2012 by The American Association of Immunologists, Inc. 0022-1767/12/$16.00 the upper dermis of recurrent herpes lesions where they show www.jimmunol.org/cgi/doi/10.4049/jimmunol.1103450 The Journal of Immunology 4159 evidence of IFN-a production and are in contact with activated general, short peptides are weak immunogens, so they need to be NK cells and lymphocytes (17). They produce IFN-a in response administered with adjuvants. To enhance the immunogenicity of to stimulation with HSV, to limit viral spread (18–21), and can our gD2 peptides, they were conjugated to dipalmitoyl-S-glyceryl present Ag to naive effector and regulatory lymphocytes (21–24). cysteine (Pam2Cys) (42), which binds specifically to and stim- Like DCs, NK cells can bridge the innate and adaptive immune ulates via TLR2 and its heterodimeric partner TLR6 and induces responses. In humans, there are two main NK subsets: the first and maturation in DCs (43–46) (some HSV strains also target TLR2 well-characterized CD56dimCD16+ NKs make up .95% of those naturally). in blood and readily lyse malignant or virally infected cells but are In preliminary experiments, we determined that these lipopep- low cytokine secretors. In contrast, the more recently described tides markedly enhanced HSV-specific CD4 T lymphocyte IFN-g CD56brightCD162 NK cells produce large amounts of cytokines, responses. Therefore, we examined the mechanism of these re- such as TNF-a and IFN-g, upon stimulation, but they only acquire sponses and then compared them with those of endogenous cytotoxicity after prolonged activation. DCs and NK cells often TLR2 stimulation by whole HSV as UV-inactivated Ag. Initi- colocalize and are able to interact both at sites of inflammation ally, the HSV2 186 strain, previously shown to stimulate se- and in lymph nodes (25, 26). In DC–NK cell interactions, cyto- quentially via TLR2 and 9, was used, followed by an HSV1 strain kines, such as IL-12, IFN-a, and IL-15, are important, but direct also shown to stimulate via TLR2. Both types of Ags, UV- cell-to-cell contacts also seem to be essential in promoting full NK inactivated HSV (UV-HSV) and Pam2Cys–gD2 peptides, are activation by DCs (27). The CD56brightCD162 subset can also act also known to stimulate maturation of human MDDCs (47, 48).
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