Biography

Name:	Ondřej Štěpánek
Nationality:	Czech
E-mail:	ondrej.stepanek@img.cas.cz

Education

2007-2011	Faculty of Science, Charles University Prague, Czech Republic Immunology, degree: PhD. (no grading or distinctions applicable)
2002-2007	Faculty of Science, Charles University Prague, Czech Republic Biology, Molecular Biology, Mgr. (eq. MA), Summa Cum Laude (highest honors, top 2%)
2002-2005	Faculty of International Relations, University of Economics Prague, Czech Republic International Economic Relations, Bc. (eq. BA), Summa Cum laude (highest honors)

Research appointments

2016-present	Head, Laboratory of Adaptive Immunity Institute of Molecular Genetics, Czech Academy of Sciences, Prague, Czech Rep.
2012-2016	Postdoc, Transplantation Immunology and Nephrology, Advisor: Prof. Ed Palmer Department of Biomedicine, University of Basel & University Hospital Basel, Switzerland
2011-2012	Postdoc, Department of Molecular Immunology, Advisor: Prof. Václav Hořejší Institute of Molecular Genetics, Czech Academy of Sciences, Prague, Czech Rep.
2007-2011	PhD student, Department of Molecular Immunology, Supervisor: Dr. Tomáš Brdička Institute of Molecular Genetics, Czech Academy of Sciences, Prague, Czech Rep.
2004-2007	MA student, Yeast Colony Group, Supervisor: Prof. Zdena Palková Faculty of Science, Charles University, Prague, Czech Rep.

Lecturing

2007-2012	Molecular and Cell Biology for Biophysicists (contribution: 100%) MA level, Faculty of Mathematics and Physics, Charles University, Prague
2007-2012	Molecular and Cell Biology Methods (contribution: 15%) BA/MA level, Faculty of Science, Charles University, Prague
2011	Theory of Methods in Immunology (contribution: 15%) MA level, Faculty of Science, Charles University, Prague
2005-2006	Seminar of Cell Biology (contribution: 100%) Johannes Kepler Grammar School, Prague, Czech Republic

Grants

2016	Forschungsfonds Nachwusforschende, University of Basel, Switzerland
2016-2018	Czech Science Agency (GAČR): Junior Grant
2016-2018	(ev. to 2020) EMBO Installation Grant
2016	Small Grant by EMBO Council
2016-2021	PROMYS Grant by Swiss National Science Foundation

Awards

Swiss Transplant Research Award 2015: 1st prize for basic research (awarded by Swiss Transplantation Society) Award for the Best Publication at the Department of Biomedicine, University Basel (59 research groups) in 2014 Award for the Best Publication in basic research in 2013, awarded by Czech Society for Analytical Cytology Jaroslav Šterzl Award for the Best Publication by a young investigator in 2013, awarded by Czech Immunological Society Award for the 2nd best publication in basic research in 2012, awarded by Czech Society for Analytical Cytology Milan Pospíšil Award for the Best Research Articles in the field of innate and anti-tumor immunity in 2011, 2nd place, awarded by the Czech Immunological Society Annual award for best research articles of the Institute of Molecular Genetics, Prague (23 research groups) in 2011: 1st place (member of the collective of authors), 3rd place (member of the collective of authors) Travel awards: 6th Leukocyte Signal Transduction Workshop, Greece (2011), 7th Leukocyte Signal Transduction Conference, Greece (2013), EMBO conference: Lymphocyte Signaling, Italy (2014)

Research Publications

• Peltzer N., Darding M., Montinaro A., Draber P., Draberova H., Kupka S., Rieser E., Fisher A., Hutchinson C., Taraborrelli L., Hartwig T., Lafont E., Haas TL., Shimizu Y., Böiers C., Sarr A., Rickard J., Alvarez-Diaz S., Ashworth MT., Beal A., Enver T., Bertin J., Kaiser W., Strasser A., Silke J., Bouillet P., Walczak H.: LUBAC is essential for embryogenesis by preventing cell death and enabling haematopoiesis. Nature. 2018 557(7703): 112-117.
• Drobek A., Moudra A., Mueller D., Huranova M., Horkova V., Pribikova P., Ivanek R., Oberle S., Zehn D., McCoy KD., Draber P., Stepanek O.: Strong homeostatic TCR signals induce formation of self-tolerant virtual memory CD8 T cells. EMBO J. 2018 e98518. [PDF]
• Drobek A., Moudra A., Mueller D., Huranova M., Horkova V., Pribikova P., Ivanek R., Oberle S., Zehn D., McCoy KD., Draber P., Stepanek O.: Strong homeostatic TCR signals induce formation of self-tolerant virtual memory CD8 T cells. bioRxiv. 2017 October 13.
• Bosch AJT., Bolinger B., Keck S., Stepanek O., Ozga AJ., Galati-Fournier V., Stein JV., Palmer E.: A minimum number of autoimmune T cells to induce autoimmunity? Cell Immunol. 2017 316: 21-31.
• Huranova M., Stepanek O.: Role of actin cytoskeleton at multiple levels of T cell activation AIMS. Molecular Science. 2016 3(4):585-596.
• Palmer, E., Drobek, A., Stepanek O. Opposing effects of actin signaling and LFA-1 on establishing the affinity threshold for inducing effector T-cell responses in mice. Eur. J. Immunol. Aug 2016;46: 1887–1901.
• Stepanek O., Prabhakar AS., Osswald C., King CG., Bulek A., Naeher D., Beaufils-Hugot M., Abanto ML., Galati V., Hausmann B., Lang R., Cole DK., Huseby ES., Sewell AK., Chakraborty AK., Palmer E. Coreceptor scanning by the T-cell receptor provides a kinetic proofreading mechanism for T cell tolerance. Cell. 2014 Oct 9;159(2):333-45.
• Stepanek O.*, Draber P.*, Horejsi V. Palmitoylated transmembrane adaptor proteins in leukocyte signaling. Cell Signal. 2014 May;26(5):895-902. Review.
• Stepanek O., Draber P., Drobek A., Horejsi V., Brdicka T. Nonredundant roles of Src-family kinases and Syk in the initiation of B-cell antigen receptor signaling. J Immunol. 2013 Feb 15;190(4):1807-18.
• Draber P.*, Stepanek O.*, Hrdinka M., Drobek A., Chmatal L., Mala L., Ormsby T., Angelisova P., Horejsi V., Brdicka T. LST1/A is a myeloid leukocyte-specific transmembrane adaptor protein recruiting protein tyrosine phosphatases SHP-1 and SHP-2 to the plasma membrane. Journal of Biological Chemistry. 2012 Jun 29;287(27):22812-21.
• Draber P., Vonkova I., Stepanek O., Hrdinka M., Kucova, M., Skopcova T., Otahal P., Angelisova P., Horejsi V., Yeung M., Weiss A., Brdicka T. SCIMP: transmembrane adaptor protein involved in MHCII signaling. Molecular and Cellular Biology. Nov 2011;31(22):4550-62.
• Stepanek O., Kalina T., Draber P., Skopcova T., Svojgr K., Angelisova P., Horejsi V., Weiss A., Brdicka, T. Regulation of Src-family kinases involved in T-cell receptor signaling by protein tyrosine phosphatase CD148. Journal of Biological Chemistry. 2011 Jun 24;286(25):22101-12.
• Stepanek O., Brdicka T., Angelisova, P., Horvath, O., Spicka J., Stockbauer P., Man P., Horejsi, V. (2011) Interaction of late apoptotic and necrotic cells with vitronectin. PlosOne. 2011 May 4;6(5):e19243.
• Hrdinka, M., Draber, P., Stepanek O., Ormsby, T., Otahal, P., Angelisova, P., Brdicka, T., Paces J., Horejsi, V., Drbal, K. PRR7 is a transmembrane adaptor protein expressed in activated T cells involved in regulation of T cell receptor (TCR) signaling and apoptosis. Journal of Biological Chemistry. 2011 Jun 3;286(22):19617-29.

 

*equally contributing authors

Research Interests

Adaptive immunity, lymphocyte development, immunological tolerance, T cell receptor signaling, T cell fate decisions, autoimmunity, immune regulations, T cell homeostasis, cytotoxic T cells, regulatory T cells

Our research focuses on understanding of how antigenic signals determine fate decisions of T cells during their development, homeostasis, and immune responses. We cover a wide range of processes, from molecular determinants of T cell responses to cellular interactions in animal models of infection and autoimmunity. At the moment, we are working on three specific projects in the field of regulatory T cells, formation of self-tolerant and immune-sufficient T cell repertoire, and origin and function of ‘virtual’ memory T cells. The long-term aim of our lab is to understand how T cell receptor signals are initiated and how the primary sequence of TCR-encoding genes predetermines various T cell fate decisions during a life-time of an individual.

1. Hyperactivity of self-reactive CD8+ T cells and impaired immune suppression by regulatory T cells (Tregs) are believed to be associated with the development of certain autoimmune disorders, like type I diabetes or multiple sclerosis. We would like to elucidate whether there is a link between these two phenomena, i.e whether regulatory T cells prevent autoimmunity by suppressing self-reactive CD8+ T cells.

For this project, we use an animal model of experimental type I diabetes, based on adoptive transfer of ovalbumin-reactive monoclonal CD8+ OT-I T cells into a transgenic RIP.OVA host expressing ovalbumin in insulin-secreting cells. After being primed with ovalbumin or related antigen, OT-I eventually differentiate into tissue infiltrating effector T cells and induce lethal autoimmunity. By comparing Treg-replete or -depleted hosts, we investigate whether Tregs establish peripheral tolerance by increasing the self-antigen dose, the self-antigen affinity, and/or the number of precursor self-reactive cells required for the onset of autoimmunity. Moreover, we elucidate how conventional CD4+ T cells influence the activation and effector function of self-reactive CD8+ T cells. In the next step, we are going to uncover suppressive mechanisms (e.g. IL-2 stealing, direct killing, inhibiting costimulation) that Tregs use to prevent CD8+ T cell-mediated cytotoxicity.

2. We have previously shown that the interaction between a kinase, Lck and CD4 or CD8 T-cell coreceptors plays a crucial role for setting the threshold for negative selection of thymocytes and establishing the central immunological tolerance. Now, we are investigating the importance of the stoichiometry of the Lck-CD4 and Lck-CD8 for fate decisions made by mature T cells. Our preliminary data indicate that the Lck-CD4 and Lck-CD8 coupling frequency is dynamically regulated during T cell development. Our mathematical model predicts that CD8+ T cells, but not CD4+ T cells, increase their responsiveness to antigens at or just below the affinity threshold for negative selection. We hypothesize that the evolution tuned the stoichiometry of the Lck-CD4 and Lck-CD8 interaction to achieve optimal balance between self-tolerance and efficient responses to tumors and pathogens independently for CD8+ cytotoxic and CD4+ helper T cells. We are now addressing these predictions experimentally using various approaches focused on T cell activation and signal transduction, T cell homeostasis, autoimmunity, anti-tumor and anti-bacterial response.

3. Recent studies have revealed that T cell homeostasis plays an important role in immune responses towards self- and foreign-antigens. However, the mechanisms underlying T cell homeostasis and subsequent immune responses are incompletely understood.

So far enigmatic ‘virtual’ memory CD8+ T cells show memory-like phenotype, but they are generated via an unknown homeostatic process and thus, do not represent true immunological memory. Other studies have shown that self-reactivity of T cells largely determines how particular clones respond during immune responses against invading pathogens.

Based on our preliminary data, we hypothesize that the ‘virtual’ memory T cells originate from naïve peripheral T cells with relatively high self-reactivity. We are now addressing this hypothesis using a panel of approaches involving in vitro and in vivo activation of transgenic monoclonal T cells, in vivo models of autoimmunity and infection, global gene expression profiling and deep TCR sequencing. We also aim to elucidate whether ‘virtual’ memory T cells exist in humans.

Group Members