Abstract
Immune responses initiated in the skin can be extremely powerful at both a local and systemic level. One of the milestones in elucidating the mechanisms underlying this phenomenon was the discovery of the T cell response-inducing function of Langerhans cells (LC). In the meantime, we know that the family of dendritic antigen-presenting cells in the skin is much bigger and, in addition to LC, includes dermal dendritic cells (DDC), CD141 + DC, CD14 + DC, inflammatory DC and plasmacytoid DC. Depending on the cellular and molecular milieu, these cells can function as either sensitizing or tolerizing elements. Signals transmitted from (innate) receptors recognizing damage- or pathogen-associated patterns are involved in directing these different functions in DC. Toll-like pathogen recognition receptors (TLR) have been particularly well investigated in this regard. The distinct distribution of TLR on LC and other DC subsets allows the immune system to elegantly orchestrate the regulatory and pro-inflammatory functions of these cells. Intriguingly, TLR signaling in DC/LC not only allows to initiate adaptive immune responses, but also directly induces innate effector functions. This is demonstrated by our findings on the mechanisms underlying basal cell carcinoma (BCC) regression upon treatment with the pharmacological TLR7 agonist imiquimod. We observed that in imiquimod-treated BCC, plasmacytoid DC directly kill tumor cells via the apoptosis-inducing molecule TRAIL. Melanoma cells can also become TRAIL-susceptible, but the magnitude of this phenomenon varies from patient to patient. Our recent findings show that TRAIL susceptibility of melanoma cell lines can be increased upon exposure to the anti-inflammatory compound diclofenac.
Taken together, we begin to understand the exact position of LC and DC in the highly complex circuits of the immune system in the skin and how these cells could be manipulated for therapeutic purposes.
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Abbreviations
- APC:
-
Antigen-presenting cell
- BCC:
-
Basal cell carcinoma
- CHS:
-
Contact hypersensitivity
- DC:
-
Dendritic cell
- DDC:
-
Dermal dendritic cell
- dsRNA:
-
Double-strain RNA
- LC:
-
Langerhans cell
- LPS:
-
Lipopolysaccharides
- LTA:
-
Lipotechoic acid
- MHC:
-
Majory histocompatibility complex
- PAMP:
-
Pathogen-associated molecular pattern
- pDC:
-
Plasmacytoid dendritic cell
- PRR:
-
Pattern recognition receptor
- S. :
-
Staphylococcus
- ssRNA:
-
Single-stranded RNA
- TLR:
-
Toll-like receptor
- TRAIL:
-
Tumor necrosis factor related apoptosis inducing ligand
- UV:
-
Ultraviolet
- poly I:C:
-
Polyinosinic:polycytidylic acid
References
Jenner E. An inquiry into the causes and effects of the variolae vaccinae, a disease discovered in some of the western countries of England, particularly Gloucestershire, and known by the name of “the Cow Pox”. 1798. Reprinted by Milan: R Lier & Co, 1923:84
Besredka A, Gross L. De l’immunisation contre le sarcome de la souris par la voie intracutanée. Ann Inst Past. 1935;55:491–500.
Braathen LR, Thorsby E. Studies on human epidermal Langerhans cells. I. Allo-activating and antigen-presenting capacity. Scand J Immunol. 1980;11(4):401–8.
Stingl G et al. The functional role of Langerhans cells. J Invest Dermatol. 1980;74(5):315–8.
Streilein JW et al. Tolerance or hypersensitivity to 2,4-dinitro-1-fluorobenzene: the role of Langerhans cell density within epidermis. J Invest Dermatol. 1980;74(5):319–22.
Schuler G, Steinman RM. Murine epidermal Langerhans cells mature into potent immunostimulatory dendritic cells in vitro. J Exp Med. 1985;161(3):526–46.
Seneschal J et al. Human epidermal Langerhans cells maintain immune homeostasis in skin by activating skin resident regulatory T cells. Immunity. 2012;36(5):873–84.
Stary G et al. Glucocorticosteroids modify Langerhans cells to produce TGF-beta and expand regulatory T cells. J Immunol. 2011;186(1):103–12.
Loser K et al. Epidermal RANKL controls regulatory T-cell numbers via activation of dendritic cells. Nat Med. 2006;12(12):1372–9.
Kaplan DH et al. Epidermal Langerhans cell-deficient mice develop enhanced contact hypersensitivity. Immunity. 2005;23(6):611–20.
Haniffa M et al. Human tissues contain CD141hi cross-presenting dendritic cells with functional homology to mouse CD103+ nonlymphoid dendritic cells. Immunity. 2012;37(1):60–73.
Jongbloed SL et al. Human CD141+ (BDCA-3) + dendritic cells (DCs) represent a unique myeloid DC subset that cross-presents necrotic cell antigens. J Exp Med. 2010;207(6):1247–60.
Collin M, McGovern N, Haniffa M. Human dendritic cell subsets. Immunology. 2013;140(1):22–30.
Merad M et al. The dendritic cell lineage: ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting. Annu Rev Immunol. 2013;31:563–604.
Palm NW, Medzhitov R. Pattern recognition receptors and control of adaptive immunity. Immunol Rev. 2009;227(1):221–33.
de Koning HD et al. Pattern recognition receptors in infectious skin diseases. Microbes Infect. 2012;14(11):881–93.
Lebre MC et al. Human keratinocytes express functional Toll-like receptor 3, 4, 5, and 9. J Invest Dermatol. 2007;127(2):331–41.
Flacher V et al. Human Langerhans cells express a specific TLR profile and differentially respond to viruses and gram-positive bacteria. J Immunol. 2006;177(11):7959–67.
Takeuchi J et al. Down-regulation of Toll-like receptor expression in monocyte-derived Langerhans cell-like cells: implications of low-responsiveness to bacterial components in the epidermal Langerhans cells. Biochem Biophys Res Commun. 2003;306(3):674–9.
Oosterhoff D et al. Intradermal delivery of TLR agonists in a human explant skin model: preferential activation of migratory dendritic cells by polyribosinic-polyribocytidylic acid and peptidoglycans. J Immunol. 2013;190(7):3338–45.
van der Aar AM et al. Loss of TLR2, TLR4, and TLR5 on Langerhans cells abolishes bacterial recognition. J Immunol. 2007;178(4):1986–90.
Enk AH et al. Inhibition of Langerhans cell antigen-presenting function by IL-10. A role for IL-10 in induction of tolerance. J Immunol. 1993;151(5):2390–8.
Lai Y et al. Commensal bacteria regulate Toll-like receptor 3-dependent inflammation after skin injury. Nat Med. 2009;15(12):1377–82.
Lai Y et al. Activation of TLR2 by a small molecule produced by Staphylococcus epidermidis increases antimicrobial defense against bacterial skin infections. J Invest Dermatol. 2010;130(9):2211–21.
Gilliet M, Cao W, Liu YJ. Plasmacytoid dendritic cells: sensing nucleic acids in viral infection and autoimmune diseases. Nat Rev Immunol. 2008;8(8):594–606.
Sugita K et al. Innate immunity mediated by epidermal keratinocytes promotes acquired immunity involving Langerhans cells and T cells in the skin. Clin Exp Immunol. 2007;147(1):176–83.
van der Aar AM et al. Cutting edge: virus selectively primes human Langerhans cells for CD70 expression promoting CD8+ T cell responses. J Immunol. 2011;187(7):3488–92.
Martin SF et al. Toll-like receptor and IL-12 signaling control susceptibility to contact hypersensitivity. J Exp Med. 2008;205(9):2151–62.
Enk AH, Katz SI. Early molecular events in the induction phase of contact sensitivity. Proc Natl Acad Sci U S A. 1992;89(4):1398–402.
Schmidt M et al. Crucial role for human Toll-like receptor 4 in the development of contact allergy to nickel. Nat Immunol. 2010;11(9):814–9.
Haley K et al. Langerhans cells require MyD88-dependent signals for Candida albicans response but not for contact hypersensitivity or migration. J Immunol. 2012;188(9):4334–9.
Hasannejad H et al. Selective impairment of Toll-like receptor 2-mediated proinflammatory cytokine production by monocytes from patients with atopic dermatitis. J Allergy Clin Immunol. 2007;120(1):69–75.
Niebuhr M et al. Impaired TLR-2 expression and TLR-2-mediated cytokine secretion in macrophages from patients with atopic dermatitis. Allergy. 2009;64(11):1580–7.
Kuo IH et al. Activation of epidermal toll-like receptor 2 enhances tight junction function: implications for atopic dermatitis and skin barrier repair. J Invest Dermatol. 2013;133(4):988–98.
Hemmi H et al. Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat Immunol. 2002;3(2):196–200.
Diebold SS et al. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science. 2004;303(5663):1529–31.
Beutner KR et al. Treatment of genital warts with an immune-response modifier (imiquimod). J Am Acad Dermatol. 1998;38(2 Pt 1):230–9.
Wagstaff AJ, Perry CM. Topical imiquimod: a review of its use in the management of anogenital warts, actinic keratoses, basal cell carcinoma and other skin lesions. Drugs. 2007;67(15):2187–210.
Palamara F et al. Identification and characterization of pDC-like cells in normal mouse skin and melanomas treated with imiquimod. J Immunol. 2004;173(5):3051–61.
Stary G et al. Tumoricidal activity of TLR7/8-activated inflammatory dendritic cells. J Exp Med. 2007;204(6):1441–51.
Kalb ML et al. TRAIL(+) human plasmacytoid dendritic cells kill tumor cells in vitro: mechanisms of imiquimod- and IFN-alpha-mediated antitumor reactivity. J Immunol. 2012;188(4):1583–91.
Drobits B et al. Imiquimod clears tumors in mice independent of adaptive immunity by converting pDCs into tumor-killing effector cells. J Clin Invest. 2012;122(2):575–85.
Griffith TS et al. Intracellular regulation of TRAIL-induced apoptosis in human melanoma cells. J Immunol. 1998;161(6):2833–40.
Passante E et al. Systems analysis of apoptosis protein expression allows the case-specific prediction of cell death responsiveness of melanoma cells. Cell Death Differ. 2013;20(11):1521–31.
Fecker LF et al. Enhanced death ligand-induced apoptosis in cutaneous SCC cells by treatment with diclofenac/hyaluronic acid correlates with downregulation of c-FLIP. J Invest Dermatol. 2010;130(8):2098–109.
Tse AK et al. Indomethacin sensitizes TRAIL-resistant melanoma cells to TRAIL-induced apoptosis through ROS-mediated upregulation of death receptor 5 and downregulation of survivin. J Invest Dermatol. 2014;134(5):1397–407.
Romani N et al. Targeting skin dendritic cells to improve intradermal vaccination. Curr Top Microbiol Immunol. 2012;351:113–38.
Hawiger D et al. Dendritic cells induce peripheral T cell unresponsiveness under steady state conditions in vivo. J Exp Med. 2001;194(6):769–79.
Sancho D et al. Identification of a dendritic cell receptor that couples sensing of necrosis to immunity. Nature. 2009;458(7240):899–903.
Chatterjee B et al. Internalization and endosomal degradation of receptor-bound antigens regulate the efficiency of cross presentation by human dendritic cells. Blood. 2012;120(10):2011–20.
Li D et al. Targeting self- and foreign antigens to dendritic cells via DC-ASGPR generates IL-10-producing suppressive CD4+ T cells. J Exp Med. 2012;209(1):109–21.
Toke ER et al. Exploitation of Langerhans cells for in vivo DNA vaccine delivery into the lymph nodes. Gene Ther. 2014;21(6):566–74.
Zaric M et al. Skin dendritic cell targeting via microneedle arrays laden with antigen-encapsulated poly-D, L-lactide-co-glycolide nanoparticles induces efficient antitumor and antiviral immune responses. ACS Nano. 2013;7(3):2042–55.
Lavelle EC et al. Cholera toxin promotes the induction of regulatory T cells specific for bystander antigens by modulating dendritic cell activation. J Immunol. 2003;171(5):2384–92.
Krishnaswamy JK, Chu T, Eisenbarth SC. Beyond pattern recognition: NOD-like receptors in dendritic cells. Trends Immunol. 2013;34(5):224–33.
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Questions
Questions
-
1.
Which one of the following statements on LC in the skin is correct?
-
A.
UV-irradiation and the treatment with corticosteroids enhance the ability of LCs to induce cytotoxic T cell responses
-
B.
LC are exclusive stimulators of Th1 cells
-
C.
Under certain conditions, LC can induce the expansion of Tregs and down-regulate proliferative and cytotoxic T cell responses
-
D.
In contrast to keratinocytes, LC cannot produce any inflammatory cytokines
-
E.
LC are found in the dermis but not in the epidermis
-
A.
-
2.
Which statement regarding TLR is true?
-
A.
TLR are exclusively expressed on cells of hematopoietic origin
-
B.
While TLR signaling is a major modulator of innate immune responses, it does not have any effect on adaptive immune responses
-
C.
TLR recognizing lipids are located on the outer cell membrane while those recognizing proteins are found intracellularly
-
D.
The different DC subsets in skin express the same TLR repertoire
-
E.
TLR belong to the PRR family that includes receptors recognizing damage- and pathogen-associated molecular patterns
-
A.
-
3.
Which statement does not describe parts of the mechanism underlying the imiquimod-induced clinical regression of BCC?
-
A.
Imiquimod acts as an artificial TLR7-ligand
-
B.
Imiquimod induces pDC to kill BCC cells in a mostly TRAIL-mediated fashion
-
C.
Imiquimod induces the killer molecule TRAIL on peripheral blood pDC in an IFN-α-dependent manner
-
D.
Imiquimod-treated BCC become selectively infiltrated by NK cells
-
E.
Imiquimod application leads to the apoptosis of BCC cancer cells
-
A.
Answers
-
1.
C
-
2.
E
-
3.
D
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Stingl, G., Brüggen, MC., Vázquez-Strauss, M. (2017). Innate and Adaptive Components of the Cutaneous Immune Barrier: The Central Role of Dendritic Cells. In: Gaspari, A., Tyring, S., Kaplan, D. (eds) Clinical and Basic Immunodermatology. Springer, Cham. https://doi.org/10.1007/978-3-319-29785-9_1
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DOI: https://doi.org/10.1007/978-3-319-29785-9_1
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