Immunobiology of Innate T Cells
Müge Özkan, PhD Candidate
The immune system is commonly divided into innate and adaptive immune system. However, innate T cells bridge these two branches, as they share features with innate NK cells and of adaptive memory T cells. The most frequent and arguably the most important innate T cells are invariant Natural Killer (iNKT) cells and mucosal NKT (mNKT or MAIT) cells. Both cell types are very potent and important effector cells in a variety of immune responses. Furthermore, basically, all iNKT and mNKT cells in every human being express an almost identical antigen receptor and respond to the same antigens in a similar fashion. Therefore, their therapeutic potential is immense as one effective treatment could, in theory, be applied to every human. However, many important aspects of iNKT and mNKT cell biology have not been uncovered. Furthermore, the potential of innate T cells for therapeutic applications for a chronic inflammatory disease has not been explored so far.
Innate T cells:
The immune system is commonly divided into innate and adaptive immune system. However, innate T Cells bridge these two branches, as they share features with innate cells and adaptive memory T cells.
The most frequent and arguably the most important innate T cells are invariant Natural Killer (iNKT) cells and mucosal NKT (mNKT or MAIT) cells, which share several unique features:
(1) both cell types use a canonical TCR α-chain, Vα14 (mouse) or Vα24 (human) for iNKT cells and Vα19 (mouse) and Vα7.2 (human) for mNKT cells;
(2) this semi-invariant TCR recognizes antigens presented by a non-polymorphic MHC molecule, CD1d for iNKT cells and MR1 for mNKT cells;
(3) the antigens presented are derived largely from bacterial products, glycosphingolipid, like αGalCer, for iNKT cells and Vitamin B metabolites for mNKT cells;
(4) both types of innate T cells rapidly exert effector functions following stimulation, and by the production of copious amounts of cytokines they can impact a large variety of immune reactions; and therefore
(5) both, iNKT and mNKT cells, have been shown to be important effector cells in anti-microbial as well as autoimmune responses.
Basically, all iNKT and mNKT cells in every human being express a canonical TCR and respond to the same antigens in a similar fashion. Therefore, the therapeutic potential of these innate T cells is immense as one effective treatment could, in theory, be applied to every human.
1) The role of iNKT cells in the lung: iNKT cells play a potent, but surprisingly dichotomous role in lung inflammation: Whereas, following lung infections their Th1 response is protective, during allergic responses, like asthma, their Th2 response is deleterious. We study both types of lung inflammation side-by-side to understand how the initial iNKT cell response in the lung is regulated. As an experimental model, infection with Streptococcus pneumonia and an allergen-induced airway hypersensitivity model are used. Uncovering key regulatory mechanisms in directing iNKT cell responses in the lung will provide novel drug candidates for therapeutic applications.
2) Therapeutic potential of NKT10 cells: We recently have discovered a novel subset of iNKT cells with potent regulatory functions, due in part to their production of IL-10. These NKT10 cells are protective during autoimmune responses in the brain and the adipose tissue. We are studying the underlying mechanisms of the regulatory function of NKT10 cells in vivo in more detail. Furthermore, in preclinical studies in humanized mice, we will test the therapeutic potential of NKT10 cells in animal models of multiple sclerosis and obesity. This will be done by targeting iNKT cells in vivo and with in vitro generated NKT10 cells for cell therapy.
3) The role of mNKT cells in autoimmune diseases: Similar to iNKT cells, mNKT cells have been implicated in some bacterial infections and autoimmune responses. However, less is known about the importance of mNKT cells in various autoimmune diseases and about the underlying mechanisms than for iNKT cells. In close collaboration with clinical researchers at DEU, we will investigate these aspects for humans with a special focus on neurological and metabolic autoimmune diseases. Animal models will be employed to elucidate the underlying mechanisms.
Our laboratory is currently seeking highly motivated graduate students, post-doctoral fellows. If you are interested in advancing immunology in a top-notch, collaborative environment, then please contact by email: firstname.lastname@example.org
|Gerhard Windenger’s CV (except)
|07/15 – present||Assistant Professor; Izmir Biomedicine and Genome Center (IBG-Izmir), Izmir, Turkey.|
|05/15 – present||Visiting Scientist; La Jolla Institute for Allergy and Immunology (LJI), San Diego, CA, USA.|
|12/12 – present||Freelance Associate Editor with PLoS Biology, Cambridge, UK.|
|08/10 – 04/15||Instructor (Research Scientist); La Jolla Institute for Allergy and Immunology (LJI), San Diego, CA, USA.|
|02/05 – 07/10||Postdoctoral fellow; La Jolla Institute for Allergy and Immunology (LJI), San Diego, CA, USA.|
|07/03 – 01/05||Postdoctoral fellow; Institute for Molecular Medicine and Experimental Immunology (IMMEI), Bonn, Germany.|
|06/03||Ph.D. in Immunology; University of Heidelberg, Heidelberg, Germany|
|04/02||B.A./M.A. in Pedagogy; University of Mainz, Mainz, Germany.|
|03/99||B.S./M.S. in Biology; University of Mainz, Mainz, Germany.|
|SCIENTIFIC AWARDS AND GRANTS (last 7 years)
• EMBO Installation Grant, European Molecular Biology Organization (EMBO), Heidelberg, Germany. (2015 – 2017).
• 2236 Co-Funded Brain Circulation Scheme Fellowship, The Scientific and Technological Research Council of Turkey (TUBITAK, Ankara, Turkey) and EU 7th Frame Work Marie Curie Actions (Brussels, Belgium) (2015 – 2017).
• Freelance Associate Editor with PLoS Biology (2012 – present).
• Immune disease fellowship, Type 1 Diabetes Center at the La Jolla Institute for Allergy and Immunology (LJI), San Diego, CA (2012).
• AAI Trainee Abstract Award, The American Association of Immunologists (AAI), Bethesda, MD (2011).
• Travel Bursary award for the ‘5th International NKT/CD1 Workshop’; March 23. – 27th 2009; Kamakura, Japan (2009)
• Marie Curie Outgoing International Fellowship (OIF), FP6-2005, European Commission Research Directorate General, Brussels, Belgium (2006, 2007, 2011).
|PUBLICATIONS (last 7 years)
Full list and citations: Google Scholar: Gerhard Wingender
• Wingender G: From the deep sea to everywhere: Environmental antigens for iNKT cells; Arch Immunol Ther Exp, in press.
• Wingender G & Kronenberg M: Characterization of human T cell subsets via surface markers, Cytometry A, 87A: 1067-1069.
• Wingender G, Sag D, Kronenberg M: NKT10 cells: a novel iNKT cell subset; Oncotarget, 6: 26552-26553.
• Wingender G, Birkholz AM, Sag D, Farber E, Chitale S, Howell AR, Kronenberg M: Selective conditions are required for the induction of iNKT cell hypo-responsiveness by antigenic stimulation; J Immunol, 2015, J Immunol, 195: 3838-3848.
• Birkholz AM, Girardi E, Wingender G, Khurana A, Wang J, Zhao M, Zahner S, Illarionov PA, Wen X, Li M, Yuan, W, Porcelli SA, Besra GS, Zajonc DM, Kronenberg M: A Novel Glycolipid Antigen for NKT Cells That Preferentially Induces IFN-α Production; 2015, J Immunol, 195, 924-933.
• Sag D, Krause P, Hedrick CC, Kronenberg M, Wingender G: IL-10-producing NKT10 cells are a distinct regulatory invariant NKT cell subset; 2014, J Clin Invest; 124, 3725-3740.
• Peukert K, Wingender G, Patecki M, Wagner S, Schmitt R, Ge S, Schwarz A, Kronenberg M, Haller H, von Vietinghoff S: Invariant natural killer T cells are depleted in renal impairment and recover after kidney transplantation, 2014, Nephrol. Dial. Transplant, 29, 1020-1028.
• Riediger CE, Wingender G, Knolle P, Bläker H, Aulmann S, Stremmel W, Encke J: Dendritic cell based immunotherapy of colorectal cancer with a Flt3 ligand adenoviral vector in a BALB/c mouse model, 2013, J Cancer Res Clin Oncol, 139, 2097-2110.
• Sag D, Wingender G, Nowyhed H, Wu R, Gebre AK, Parks JS, Kronenberg M, Hedrick CC: ATP-binding cassette transporter G1 intrinsically regulates invariant NKT cell development, 2012, J Immunol, 189, 5129-5138.
• Wingender G, Stepniak D, Krebs P, McBride S, Mazmanian S.K., Kronenberg M: Intestinal microbes modulate the phenotype and function of mouse invariant natural killer T cells; 2012, Gastroenterology, 143, 418-428.
Featuring commentary: Coppieters KT and Elewaut D: Natural Killer T cells: Born in the thymus, raised in the gut; 2012, Gastroenterology, 143, 293-296.
• Windenger G, Hiss M, Engel I, Ley K, Haller H, Kronenberg M, von Vietinghoff S: Neutrophilic granulocytes modulate invariant natural killer T cell function in mice and humans; 2012, J Immunol, 188, 3000-3008.
• Kisseleva T, von Köckritz-Blickwede M, Reichart D, McGillivray S, Wingender G, Kronenberg M, Glass C, Nizet V, Brenner D: Fibrocyte-like cells recruited to the spleen support innate and adaptive immune responses to acute injury or infection, 2011, J Mol Med, 89, 997-1013.
• Wingender G, Rogers P, Batzer G, Lee MS, Bai D, Pei B, Khurana A, Kronenberg M, Horner AA: Invariant NKT cells are required for airway inflammation induced by environmental antigens; 2011, J Exp Med, 208, 1151-1162.
Featuring cover art and featuring commentary: Godfrey DI and Rossjohn J: New ways to turn on NKT cells; 2011, J Exp Med, 208, 1121-1125. Featured by: Nature (9 June 2011, Vol. 474) and J Allergy Clin Immunol (August 2011, Vol. 128).
• Wingender G, Krebs P, Beutler B, Kronenberg M: Antigen-specific cytotoxicity by invariant NKT cells in vivo is CD95/CD178 dependent and is correlated with antigenic potency; 2010, J Immunol, 185, 2721-2729.
• Wei B, Wingender G, Fujiwara D, Chen DY, McPherson M, Brewer S, Kronenberg M, Braun J: Commensal microbiota and CD8+ T cells shape the formation of invariant NKT cells; 2010, J Immunol, 184, 1218-1226.
• Sullivan BA, Nagarajan NA, Wingender G, Wang J, Scott I, Tsuji M, Franck RW, Porcelli S, Zajon D and Kronenberg M: Mechanisms for glycolipid antigen-driven cytokine polarization by Vα14i NKT cells; 2010, J Immunol, 181, 141-153.
• Wingender G and Kronenberg M: The role of canonical Natural Killer T cells in mucosal immunity and inflammation; 2008, Am J Pathol, 294: G1-8.
• Wingender G & Kronenberg M: Chapter 8. The role of invariant Natural Killer T cells in autoimmune diseases; 103-129; In: The Autoimmune Diseases (5th edition), 2014; edited by Noel R. Rose and Ian R. Mackay.