Mechanisms controlling Th17 and regulatory T cells in the anti-Leishmania response

Abstract:

Protective immunity against cutaneous leishmaniasis is dependent on the development of IFN+ Th1 and Tc1 cells. In contrast, regulatory T cells (Treg) promote parasite persistence. In addition, IL-17A-mediated enhanced neutrophil recruitment is in part responsible for susceptibility. An effective vaccine against this important human disease is not available. In order to learn how to modulate T cell regulation in infectious diseases using the model pathogen L. major, we now plan to investigate the role of proinflammatory cytokines for the differentiation of Th17 and Treg and their function for induction and maintenance of protective immunity against L. major. In addition, we plan to investigate how cytokines produced by effector T cells modulate the skin response during leishmaniasis.

Principal investigators:

Univ.-Prof. Dr. med. Esther von Stebut-Borschitz
Klinik für Dermatologie und Venerologie
Uniklinik Köln
Kerpener Straße 62, 50937 Köln
Phone: +49 (0)221 478-82245
E-mail: Esther.von-Stebut@uk-koeln.de
Web: http://www.hautklinik-mainz.de/hautklinik/clinical-research-center-crc/crc-fuer-patienten/wissenschaftler/ag-univ-prof-von-stebut-borschitz.html /
https://dermatologie.uk-koeln.de

Univ.-Prof. PhD Ari Waisman
Institut für Molekulare Medizin
Universitätsmedizin der Johannes Gutenberg-Universität Mainz
Obere Zahlbacher Straße 67, 55131 Mainz
Phone: +49 (0)6131 17-9129
E-mail: waisman@uni-mainz.de
Web: http://www.unimedizin-mainz.de/molekulare-medizin/research-groups/ag-waisman.html?L=1

Doctoral candidate:

Theresa Schaller

Postdoc:

Dr. Nir Yogev

Project-related publications:

Mufazalov IA, Schelmbauer C, Regen T, Kuschmann J, Wanke F, Gabriel LA, Hauptmann J, Müller W, Pinteaux E, Kurschus FC, Waisman A (2017) IL-1 signaling is critical for expansion but not generation of autoreactive GM-CSF+ Th17 cells. EMBO J 36:102

Heink S, Yogev N, Garbers C, Herwerth M, Aly L, Gasperi C, Husterer V, Croxford AL, Möller-Hackbarth K, Bartsch HS, Sotlar K, Krebs S, Regen T, Blum H, Hemmer B, Misgeld T, Wunderlich TF, Hidalgo J, Oukka M, Rose-John S, Schmidt-Supprian M, Waisman A*, Korn T* (2017) Trans-presentation of IL-6 by dendritic cells is required for the priming of pathogenic TH17 cells. Nat Immunol 18:74 (* joint senior authors)

Dietze-Schwonberg K, Lorenz B, Lopez Kostka S, Waisman A, von Stebut E (2016) Parasite clearance in leishmaniasis in resistant animals is independent of the IL-23/IL-17A axis. J Invest Dermatol 136:1906

Bruttger J, Karram K, Wörtge S, Regen T, Marini F, Hoppmann N, Klein M, Blank T, Yona S, Wolf Y, Mack M, Pinteaux E, Müller W, Zipp F, Binder H, Bopp T, Prinz M, Jung S, Waisman A (2015) Genetic cell ablation reveals clusters of local self-renewing microglia in the mammalian central nervous system. Immunity 43:92

Brosch S, Dietze-Schwonberg K, Lopez Kostka S, Lorenz B, Haak S, Becher B, von Stebut E (2015) Disease control in cutaneous leishmaniasis is independent of IL-22. J Invest Dermatol 135:308

El Malki K, Karbach SH, Huppert J, Zayoud M, Reissig S, Schüler R, Nikolaev A, Karram K, Münzel T, Kuhlmann CR, Luhmann HJ, von Stebut E, Wörtge S, Kurschus FC, Waisman A (2013) An alternative pathway of imiquimod-induced psoriasis-like skin inflammation in the absence of interleukin-17 receptor a signaling. J Invest Dermatol 133:441-451

Kautz-Neu K, Lopez Kostka S, Dinges S, Iwakura Y, Udey MC, von Stebut E (2011) A role for leukocyte-derived IL-1RA in DC homeostasis revealed by increased susceptibility of IL-1RA-deficient mice to cutaneous leishmaniasis. J Invest Dermatol 131:1650

Kautz-Neu K, Noordegraaf M, Dinges S, Bennett CL, John D, Clausen BE*, von Stebut E* (2011) Langerhans cells are negative regulators of the anti-Leishmania response. J Exp Med 208:885 (* joint senior authors)

Lopez Kostka S, Dinges S, Griewank K, Iwakura Y, Udey MC, von Stebut E (2009) IL-17 promotes progression of cutaneous leishmaniasis in susceptible mice. J Immunol 182:3039