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The T Cell Repertoire Specific for the IE-1 Protein of Human Cytomegalovirus: Diversity, Function and Evasion

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The T Cell Repertoire Specific for the IE-1 Protein of Human Cytomegalovirus: Diversity, Function and Evasion Dissertation zur Erlangung des Doktorgrades der Fakultät für Chemie und Pharmazie der Ludwig-Maximilians-Universität München The T cell repertoire specific for the IE-1 protein of human cytomegalovirus: diversity, function and evasion von Stefanie Maria Ameres aus Deggendorf, Deutschland 2012 Erklärung Diese Dissertation wurde im Sinne von §7 der Promotionsordnung vom 28. November 2011 von Herrn Prof. Dr. Wolfgang Hammerschmidt betreut und von Herrn Prof. Dr. Horst Domdey vor der Fakultät für Chemie und Pharmazie vertreten. Eidesstattliche Versicherung Diese Dissertation wurde eigenständig und ohne unerlaubte Hilfe erarbeitet. München, den 03.07.2012 Stefanie Ameres Dissertation eingereicht am 03.07.2012 1. Gutachter: Prof. Dr. Horst Domdey 2. Gutachter: Prof. Dr. Wolfgang Hammerschmidt Mündliche Prüfung am 28.01.2013 Teile dieser Arbeit werden/wurden wie folgt veröffentlicht: Ameres, S., J. Mautner, F. Schlott, M. Neuenhahn, D.H. Busch, B. Plachter, and A. Moosmann. Antigen Presentation to an Immunodominant Population of HLA-C-Restricted T Cells Resists Cytomegalovirus Immunoevasion. 2nd revision PLOS Pathogens Hesse, J., S. Ameres, K. Besold, S. Krauter, A. Moosmann, and B. Plachter. Suppression of CD8+ T-cell recognition in the immediate-early phase of human cytomegalovirus infection. Epub oct 2012. J. Gen. Virol. Teile dieser Arbeit wurden im Rahmen der Dissertation wie folgt präsentiert: May 3rd–4th, 2012 DFG SFB-TR36 Symposium "Adoptive T Cell Therapy" Berlin, Germany Talk: "CD8+ T cells overcome HCMV immunoevasion dependent on their HLA restriction" Dec. 5th–7th, 2011 DFG SFB-TR36 Retreat "Principles and Applications of Wildbad Kreuth, Adoptive T Cell therapy" Germany Talk: "CD8+ T cells defeat HCMV immunoevasins dependent on MHC restriction" May 14th–17th, 2011 13th International CMV/Betaherpesvirus Workshop Nürnberg, Germany Poster 1: "Preferential T cell control of HCMV infection through HLA-C" Poster 2: "HCMV IE-1 is recognized by a diverse repertoire of CD4+ Tcells" Oct. 6th–7th, 2010 Symposium on "Viral Offense and Immune Defense" Munich, Germany Poster: "Components and functions of the T cell repertoire against immediate-early 1 antigen of Cytomegalovirus" Sept. 26th–30th, 2010 11th International Symposium on Dendritic Cells Lugano, Switzerland Poster: "Components and functions of the T cell repertoire against immediate-early 1 antigen of Cytomegalovirus" Summary I Summary The present study investigates the diversity and function of the T cell repertoire specific for the immediate-early 1 (IE-1) antigen of HCMV and analyzes the viral countermeasures to recogni- tion of this antigen, with an aim to improve antiviral immunotherapy. Among HCMV antigens, IE-1 is a dominant target of CD8+ T cells. Superior protective function of IE-1-specific CD8+ T cells is expected because T cells recognizing immediate-early infection can destroy infected cells before these produce new virus. CD8+ and CD4+ T cells specific for IE-1 could be ex- panded in vitro from all healthy HCMV carriers by stimulation of peripheral blood cells with autologous IE-1-expressing activated B cell lines (mini-LCLs). Specific T cell clones were established from expanded T cells by limiting dilution and used to define epitope specificities and the impact of viral immunoevasion on T cells with different specificities. CD4+ T cells against IE-1 were a quantitatively small but customary component of the HCMV- specific T cell repertoire. In each donor, 3–7 IE-1 epitopes were identified (27 in total) and pre- sented by HLA-DR, DQ or DP allotypes, and some epitopes were shared between donors. CD4+ epitopes were distributed over the entire IE-1 sequence. All IE-1-specific CD4+ T cell clones produced Th1 cytokines (IL-2, IFN-γ, TNF-α), some of them also Th2 cytokines (IL-4), and only few were cytotoxic. CD4+ T cell clones had distinct reactivity against HCMV-infected dendritic cells (DCs), which was especially strong for HLA-DP-restricted clones, indicating that IE-1 presentation by different class II allotypes may be differentially regulated. The CD8+ T cell response to IE-1 was found to be extremely large and focused on 1 or 2 epitopes per donor, often shared between donors. Unexpectedly, newly identified CD8+ T cells restricted through a very frequent HLA-C allotype, C*0702, dominated the T cell response to IE- 1 in carriers of this allele, and recognized HCMV-infected cells much more efficiently than HLA- A and B-restricted T cells. Detailed analyses using HCMV strains deleted for all four or three of the HLA class I-specific immunoevasins US2/3/6/11 revealed allotype-specific patterns of interference with T cell recognition by each of US2, US3 and US11. A concerted action of se- veral immunoevasins already at the immediate-early phase of infection was necessary to block antigen presentation by most HLA-A and B allotypes. HLA-C*0702 was selectively excluded from viral immunoevasion, and CD8+ T cell recognition through HLA-C*0702 but not HLA-A or - B allotypes was specifically preserved. Conversely, killing of infected cells by NK cells carrying an HLA-C-specific inhibitory receptor was specifically inhibited. Thus, HCMV immunoevasion strikes a balance between excessive recognition by CD8+ T cells and by NK cells. As a conse- quence, HLA-C-restricted antigen presentation is selectively preserved and HLA-C-restricted T cells may be superior effectors of HCMV-specific vaccines and cellular immunotherapies. Zusammenfassung III Zusammenfassung Diese Arbeit untersucht die Diversität und Funktion des spezifischen T-Zellrepertoires gegen das Antigen immediate-early 1 (IE-1) von HCMV und die viralen Maßnahmen gegen seine Erkennung. Ziel ist die Verbesserung der antiviralen Immuntherapie. IE-1 ist ein dominantes Zielantigen HCMV-spezifischer CD8+-T-Zellen. Eine protektive Wirkung gerade IE-1-spezifi- scher T-Zellen wird erwartet, da T-Zellen gegen Antigene der IE-Phase infizierte Zellen zerstö- ren können, bevor neues Virus gebildet wird. Spezifische CD8+- und CD4+-T-Zellen gegen IE- 1 konnten in vitro aus Blut jedes gesunden HCMV-Trägers durch Stimulation mit autologen IE- 1-exprimierenden B-Zelllinien (mini-LCLs) expandiert werden. Spezifische T-Zellklone wurden hergestellt, um die Zielepitope der T-Zellen zu ermitteln und die virale Immunevasion gegen- über T-Zellen verschiedener Spezifitäten zu untersuchen. CD4+ T-Zellen gegen IE-1 waren in HCMV-Trägern zwar in geringer Zahl, jedoch regelmäßig vorhanden. Je Spender wurden 3–7 IE-1-Epitope identifiziert (27 insgesamt), die durch HLA- DR, DQ oder DP präsentiert wurden, manche dieser Epitope in mehreren Spendern. Die CD4+- T-Zellepitope waren über den Großteil der IE-1-Sequenz verteilt. IE-1-spezifische T-Zellklone sezernierten Th1-Zytokine (IL-2, IFN-γ, TNF-α), manche auch Th2-Zytokine (IL-4), nur wenige waren zytotoxisch. Alle CD4+-T-Zellklone waren ausgeprägt reaktiv gegen HCMV-infizierte dendritische Zellen (DCs), am stärksten HLA-DP-restringierte Klone, ein Hinweis auf eine differentielle Antigenpräsentation durch verschiedene Klasse-II-Allotypen. Die CD8+-T-Zellantwort gegen IE-1 erwies sich als sehr stark. Sie richtete sich gegen 1 bis 2 Epitope pro Spender, bei verschiedenen Spendern oft dieselben. Unerwartet dominierten bisher unbekannte HLA-C-restringierte CD8+-T-Zellen die Immunantwort gegen IE-1, restringiert durch den häufigen Allotyp HLA-C*0702. Solche T-Zellen erkannten die HCMV-Infektion weit effizien- ter als HLA-A- und HLA-B-restringierte T-Zellen. Untersuchungen mit HCMV-Rekombinanten, in denen alle vier oder drei der vier HLA-Klasse-I-spezifischen Immunevasine US2/3/6/11 deletiert waren, ergaben distinkte Allotyp-spezifische Muster der Inhibition der T-Zellerkennung durch US2, US3 und US11. Bei den meisten HLA-A- und HLA-B-Allotypen war die Kooperation meh- rerer Moleküle der US2/3/6/11-Gruppe in der IE-Phase der Infektion notwendig, um die Antigenpräsentation zu unterbinden. HLA-C*0702 war von der viralen Immunevasion ausgenommen, und die Erkennung durch HLA-C*0702-restringierte T-Zellen, nicht aber HLA- A/B-restringierte T-Zellen, war selektiv bewahrt. Umgekehrt war die Zytolyse von infizierten Zellen durch NK-Zellen, die einen inhibitorischen Rezeptor für HLA-C trugen, spezifisch inhibiert. Die Immunevasion durch HCMV scheint so ausbalanciert zu sein, dass eine exzessive Erkennung einerseits durch CD8+ T-Zellen, andererseits durch NK-Zellen vermieden wird. Infolgedessen wird die HLA-C-restringierte Antigenpräsentation selektiv bewahrt. Daher könn- ten HLA-C-restringierte T-Zellen besonders geeignete Effektoren einer HCMV-spezifischen Impfung oder zellulären Immuntherapie sein. Table of contents V Table of contents Summary ...................................................................................................................................................... I Zusammenfassung .................................................................................................................................... III Table of contents ....................................................................................................................................... V 1 Introduction .......................................................................................................................................... 1 1.1 Cellular immune response mechanisms .................................................................................... 1 1.1.1 Antigen presentation in the human system ............................................................................. 2 1.1.2
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