Sonderforschungsbereich 415:
"Specifity and Pathophysiology of Signal Transduction Pathways"

Project A16: »Interplay between DNA repair and cytokines: Significance for UV-induced immunosuppression«

Ultraviolet (UV) radiation exhibits the capacity to suppress the immune system and even to induce antigen specific immunotolerance. Both phenomena can be prevented and broken, respectively, by the cytokine interleukin (IL)-12. UV-induced DNA damage has been recognized as the major molecular trigger involved in the signal transduction of UV-induced immunosuppression. Based on our previous observation that IL-12 exhibits the capacity to reduce UV-induced DNA damage via induction of DNA repair, it was investigated whether the antagonization of UV-induced immunsuppression by IL-12 is mediated via its effect on DNA damage. Accordingly, IL-12 is not able to prevent UV-induced immunosuppression in DNA repair deficient (Xpa-/-) mice. IL-12 reduces the number of UV-damaged Langerhans cells in the regional lymph nodes in wild type but not in DNA repair-deficient mice. This was the first demonstration of a relation between DNA repair and the antagonization of UV-induced immunsuppression by IL-12

It is the aim of this project to clarify the further mechanisms by which IL-12 prevents UV-induced immunosuppression. In addition, the mechanisms underlying UV-induced immunosuppression especially the induction of regulatory T cells are further elucidated. Utilizing bone marrow chimera it is studied whether for the prevention of UV-induced immunosuppression IL-12 targets primarily Langerhans cells or keratinocytes. In addition, the present data imply that UV-induced tolerance is not the consequence of an apoptotic loss but of emigration of UV-damaged Langerhans cells. Thus, it is assumed that the presence of UV-damaged but still alive Langerhans cells in the regional lymph nodes is crucial for the induction of regulatory T cells. Whether this is the case, is investigated using topical steroids and high dose UV radiation as tools to completely kill Langerhans cells. Furthermore, it is studied whether IL-12 knock out mice are more susceptible to UV-induced immunosuppression than wild type mice and whether this is due to a decreased DNA repair.

Previous studies have demonstrated that the proinflammatory cytokine IL-18 is also able to reduce UV-mediated DNA damage although it does not share the same immunomodulatory capacities like IL-12. Thus, the effect of IL-18 on UV-induced immunosuppression and tolerance in wild type and DNA repair deficient mice is investigated.

These studies will provide new insights into the mechanisms of UV-induced immunosuppression and indicate strategies how this can be prevented. They will thus contribute to the further understanding of the biologic and pathologic effects of UV radiation, one of the most relevant environmental factors today.

Original papers

Majewski S, Maeda A, Jantschitsch C, Schwarz T, Schwarz A. (2010) IL-23 antagonizes UV-induced immunosuppression via two mechanisms: Reduction of UV-induced DNA damage and inhibition of UV-induced regulatory T cells.

J Invest Dermatol 130:554-562

Schwarz A, Noordegraaf M, Maeda A, Torii K, Clausen BE, Schwarz T. (2010) Langerhans Cells are required for UVR-induced immunosuppression.

J Invest Dermatol 130:1419-1427

Maeda A, Beissert S, Schwarz T, Schwarz A. (2008) Phenotypic and functional characterization of UV-induced regulatory T cells.

J Immunol 180:3065-3071

Schwarz T. (2008) 25 years UV-induced immunosuppression mediated by T cells - From disregarded T suppressor cells to highly respected regulatory T cells.

Photochem Photobiol 84:10-18

Scholz F, Schulte A, Adamski F, Hundhausen C, Schwarz A, Kruse ML, Proksch E, Ludwig A. (2007) Constitutive expression and regulated release of the transmembrane chemochine CXCL16 in human and murine skin.

Invest Dermatol 127:1444-1455

Schwarz A, Maeda A, Schwarz T. (2007) Alteration of the migratory behavior of UV-induced regulatory T cells by tissue-specific dendritic cells.

J Immunol 78:877-886

Beissert S, Schwarz A, Schwarz T. (2006) Regulatory T cells. Perspective Series.

J Invest Dermatol 126:15-24

Greinix HT, Socié G, Bacigalupo A, Holler E, Edinger MG, Apperley JF, Schwarz T, Ullrich SE, Albert ML, Knobler RM, Peritt D, Ferrara JLM. (2006) Assessing the Potential Role of Photopheresis in Hematopoietic Stem Cell Transplant

Bone Marow Transpl, Aug;38:265-73

Loser K, Mehling A, Choi Y, Loeser S, Appelt J, Kuhn A, Grabbe S, Schwarz T, Penninger JM, Beissert S. (2006) Epidermal RANKL controls homeostasis of regulatory T cells.

Nat Med 12:1372-1379

Maeda A, Schneider SW, Kojima M, Beissert S, Schwarz T, Schwarz A. (2006) Enhanced photocarcinogenesis in interleukin-12 deficient mice.

Cancer Res 66:2962-2969

Maeda A, Schneider SW, Kojima M, Beissert S, Schwarz T, Schwarz A. (2006) Enhanced photocarcinogenesis in interleukin-12 deficient mice.

Cancer Res 66:2962-2969

Schwarz A, Maeda A, Ständer S., van Steeg H, Schwarz T. (2006) Interleukin-18 reduces UV-induced DNA damage and thereby affects photoimmuno-suppression.

J Immunol 176:2896?2901

Schwarz A, Maeda A, Schwarz T. (2006) Alteration of the migratory behavior of UV-induced regulatory T cells by tissue-specific dendritic cells.

J Immunol 78:877-886

Schwarz A, Maeda A, Ständer S, van Steeg H, Schwarz T. (2006) Interleukin-18 reduces UV-induced DNA damage and thereby affects photoimmuno-suppression

J. Immunol. 176:2896-2901

Schwarz T. (2006) Effects of UV radiation on the immune system.

The Spectrum 19:12-16

Strozyk E, Pöppelmann B, Schwarz T, Kulms D. (2006) Differential effects of NF?B on apoptosis induced by DNA damaging agents - The type of DNA damage determines the final outcome.

Oncogene 25:6239-6251

Strozyk E, Pöppelmann B, Schwarz T, Kulms D. (2006) Differential effects of NFkB on apoptosis induced by DNA damaging agents - The type of DNA damaging agents - The type of DNA damage determines the final outcome.

Oncogene, 25:6239-6251

Böhm M, Wolff I, Scholzen TE, Robinson SJ, Healy E, Luger TA, Schwarz T, Schwarz A. (2005) Alpha-melanocyte-stimulating hormone protects from ultraviolet radiation-induced apoptosis and DNA damage

J.Biol. Chem. 280:5795-5802

Maeda A, Schwarz A, Kernebeck K, Gross N, Aragane Y, Peritt D, Schwarz T. (2005) Intravenous infusion of syngeneic apoptotic cells by photopheresis induces antigen-specific regulatory T cells

J. Immunol. 174: 5968-5976

Riemann H, Loser K, Beissert S, Fujita M, Schwarz A, Schwarz T, Grabbe S. (2005) IL-12 breaks dinitrothiocyanobenzene (DNTB) mediated tolerance and converts the tolerogen DNTB into an immunogen.

J. Immunol. 175:5866-5874

Schwarz A, Maeda A, Kernebeck K, van Steeg H, Beissert S, Schwarz T. (2005) Prevention of UV radiation-induced immunosuppression by IL-12 is dependent on DNA repair

J. Exp. Med. 2001:173-179

Schwarz T. (2005) Mechanisms of UV-induced immunosuppression.

Keio J Med 54:165-171

Schwarz T. (2005) Regulatory T cells induced by ultraviolet radiation.

Int Arch Allergol Immunol 137:187-193

Schwarz T. (2005) UV-induzierte regulatorische T-Zellen.

J Dtsch Dermatol Ges. 3:504-510

Weichenthal M, Schwarz T. (2005) Phototherapy - How does UV work?

Photodermatol Photoimmunol Photomed 21:260-266

Schwarz A, Maeda A, Wild MK, Kernebeck K, Gross N, Aragane Y, Beisert S, Vestweber D, Schwarz T. (2004) UV-induced regulatory T cells do not only inhibit the induction but can also suppress the effector phase of contact hypersensitivity

J. Immunol.172:1036-1043

Aragane Y, Maeda A, Schwarz A, Tezuka T, Ariizumi K, Schwarz T. (2003) Involvement of dectin-2 in UV radiation-induced tolerance

J. Immunol. 171:3801-3807

Schwarz A, Ständer S, Berneburg M, Böhm M, Kulms D, van Steeg H, Große-Heitmeyer K, Krutmann J, Schwarz T. (2002) Interleukin-12 suppresses ultraviolet radiation-induced apoptosis by inducing DNA repair.

Nat. Cell Biol. 4:26-31

Beissert S, Rühlemann D, Mohammad T, Grabbe S, El-Ghorr A, Norval M, Morrison H, Granstein R, Schwarz T. (2001) Interleukin-12 prevents the inhibitory effects of cis-urocanic acid on tumor antigen presentation by Langerhans cells: Implications for photocarcinogenesis

J. Immunol. 167:6232-6238

Reviews

Beissert S, Schwarz A, Schwarz T (2006) Regulatory T cells. Perspective Series.

J. Invest. Dermatol. 126:15-24

Schwarz T. (2005) Regulatory T cells induced by ultraviolet radiation

Int. Arch. Allergol. Immunol. 137:187-193

Schwarz T. (2005) UV-induzierte regulatorische T-Zellen

JDDG 3:504-510

Schwarz T. (2005) Ultraviolette Strahlung - Immunantwort

JDDG 3:S11-S18

Schwarz T. (2005) Mechanisms of UV-induced immunosuppression

Keio J. Med. 54:165-171

Weichenthal M, Schwarz T. (2005) Phototherapy - How does UV work?

Photodermatol. Photoimmunol. & Photomed. 21: 260-266

Schwarz T. (2003) Effekte von ultravioletter Strahlung auf das Immunsystem

JDDG 1: 142-150

Schwarz T. (2003) Skin immunity

Br. J. Dermatol. 149 (Suppl. 66):2-4