Control of Anti-viral T cell Responses by Regulatory T cells and Co-stimulatory Molecules
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- Joseph Kranz
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1 Diss. ETH Nº Control of Anti-viral T cell Responses by Regulatory T cells and Co-stimulatory Molecules A dissertation submitted to ETH ZURICH for the degree of Doctor of Sciences presented by IWANA SCHMITZ Master of Science in Biology ETH Zurich born November 25, 1982 citizen of Böttstein (AG) accepted on the recommendation of Prof. Dr. Manfred Kopf, examiner Prof. Dr. Annette Oxenius, co-examiner Dr. Stefan Freigang, co-examiner 2013
2 1. Summary 5 1. Summary Most pathogens are controlled satisfactorily by the immune system without grave consequences for the host. This is possible due to a fine-tuning of the immune response, which achieves efficient immune control and pathogen clearance but at the same time assures the maintenance of tissue integrity. Nevertheless, some pathogens cause either severe immunopathology resulting in substantial tissue damage or establish a persistent, chronic infection. For immunotherapeutic interventions, it is important to understand the mechanisms by which immune cells regulate and adjust immune responses and the reason why the immune response fails against certain pathogens. In this thesis, we investigated the contributions of regulatory T cells (Treg), cytokines and co-stimulatory and co-inhibitory receptors during lymphocytic choriomeningitis virus (LCMV) infection with the goal to better understand these immunoregulatory pathways in the defense against pathogens. The first part of the thesis focuses on the impact of Treg cells, which are key negative regulators of the immune system that protect against immunopathology by inhibiting exaggerated immune responses. However, their role during the adaptive immune response against pathogens is still not fully understood. Infection with different doses of LCMV Docile, a strain resulting in either a resolved or persistent infection depending on the infecting dose, showed that the Treg cell population expands after an initial contraction and that this Treg cell expansion was dependent on the viral load. In addition, interleukin-21 receptor (IL- 21R)-deficient mice exhibited an even stronger Treg cell proliferation, suggesting for a negative regulation of Treg cells by IL-21. Given that the expansion of Treg cells was virusdriven, the effect of Treg cells on the priming and functionality of antiviral T cells during LCMV infection was studied by using two complementary experimental approaches: a loss of function model using the DEREG mice in which Treg cells can be depleted due to transgenic expression of the diphtheria toxin receptor, and a gain of function approach using IL-2/anti- IL-2 immune complexes (IL-2ic) to expand the Treg cell population. These studies revealed that Treg cells functionally impair virus-specific CD8 + and CD4 + T cells and thereby contribute to the establishment of viral persistence. Thus, our results suggest that IL-21 prevents T cell exhaustion and viral persistence via limiting the virus-driven Treg cell proliferation.
3 6 1. Summary In a side project, the redundancy of the cytokines IL-21 and IL-2 was investigated during acute LCMV infection, as both, IL-21 and IL-2 are required for optimal CD8 + T cell memory responses during chronic infections but appear to be dispensable during acute infection. The use of mixed bone marrow (BM) chimeric mice allowed to compare the requirement of IL-2R, IL-21R or both for priming, effector function and memory responses of CD8 + T cells. Furthermore it enabled us to determine whether the lacking effect of either cytokine on the primary immune response of CD8 + T cell during acute infection was due to a compensatory role of IL-2 and IL-21. Analysis of the BM chimeric mice indicated that IL-2 and IL-21 could partially compensate for each other s function. Both, IL-2 and IL-21 did not affect the priming of CD8 + T cells but were crucial for a fully functional memory CD8 + T cell immune response upon acute LCMV infection. The second part of the thesis aimed to elucidate the complex signaling network of the surface co-regulatory receptor herpesvirus entry mediator (HVEM) during viral infections. HVEM positively and negatively regulates the extent and duration of T cell activation by interacting with several partners, including B and T lymphocyte attenuator (BTLA) and LIGHT (lymphotoxin-like, inducible expression, competes with herpes simplex virus glycoprotein D for HVEM, a receptor expressed by T lymphocytes). The HVEM signaling induced by LIGHT has been mainly described to promote pro-inflammatory immune responses, whereas activation of HVEM by BTLA provides an inhibitory signal. So far, most studies investigated the interaction of HVEM in vitro; hence little is known about their role during infections. The present thesis conducted a thorough comparison of the anti-viral T cell responses in HVEM-, LIGHT-, and BTLA-deficient mice in response to infection with LCMV. This analysis showed normal T cell priming, expansion and memory responses in mice lacking one of these receptors during an acute LCMV infection. However, absence of HVEM or BTLA resulted in an impaired viral clearance of a persistence-prone virus strain, suggesting that HVEM-BTLA interactions contribute to the immune control of chronic infections. The fact that normal anti-viral T cell responses were detected in HVEM- or BTLA-deficient mice suggests a potential requirement of HVEM and BTLA for the humoral immune response. In addition, we found a less prominent contraction of the Treg cell population in LIGHT-deficient mice after LCMV Docile infection. As Treg cells of HVEM-deficient mice were unaltered, LIGHT might promote the Treg cell decline via its other binding partner
4 1. Summary 7 LTβR. In spite of the altered Treg cell contraction, no impact on the immune response was detected, which leaves the role of the Treg cell decline unsolved. Overall, the data of this thesis revealed that the regulation of Treg cells by IL-21 is crucial for the outcome of a viral infection and suggest that HVEM interactions predominantly contribute to the control of chronic viral infections.
5 8 2. Zusammenfassung 2. Zusammenfassung Die meisten Krankheitserreger werden vom Immunsystem ohne schwerwiegende Konsequenzen gut kontrolliert. Dies ist nur dank einer feinen Regulierung der Immunantwort möglich, die den Erreger klärt und gleichzeitig die Gewebsstrukturen intakt hält. Es gibt jedoch Erreger, die eine defekte Immunantwort auslösen und erhebliche Gewebsschäden oder eine chronische Infektion verursachen. Um eine entsprechende Therapie für solche Erreger zu finden, ist es wichtig die Mechanismen zu verstehen mit welchen die Immunzellen die Immunantwort ausgleichen und regulieren und den Grund für das Fehlschlagen dieser Antwort gegen gewisse Erreger zu erkennen. In der vorliegenden Arbeit wurde das Zusammenspiel von regulatorischen T Zellen (Treg), bestimmten Zytokinen und costimulatorischen und co-inhibitorischen Rezeptoren während der Infektion mit dem Virus der lymphozytären Choriomeningitis (LCMV) mit dem Ziel untersucht, diese Mechanismen der antiviralen Immunabwehr besser zu verstehen. Der erste Teil dieser Arbeit fokussiert auf die Auswirkung von regulatorischen T Zellen auf das Immunsystem. Regulatorische T Zellen sind wichtige negative Regulatoren, welche eine überschiessende Immunaktivierung verhindern, um den Organismus vor einer Immunpathologie zu schützen. Ihre Rolle während der adaptiven Immunantwort gegen Pathogene ist jedoch noch nicht ganz verstanden. Die Infektion mit dem LCMV Stamm Docile führt, in Abhängigkeit von der Virusdosis, zu einer klärenden oder zu einer chronischen Infektion. Unsere Analyse zeigte, dass die Population der regulatorischen T Zellen nach einer anfänglichen Kontraktion, dosisabhängig expandieren. In Interleukin-21 Rezeptor (IL-21R) knockout Mäusen wurde eine noch stärkere Expansion der regulatorischen T Zellen beobachtet, was auf eine Regulation von IL-21 auf die regulatorischen T Zellen hinweist. Da die Expansion der regulatorischen T Zellen Virus getrieben war, wurde der Effekt der regulatorischen T Zellen auf das Priming und die Funktionalität der anti-viralen T Zellen während einer LCMV Infektion erforscht. Dazu wurden zwei komplementäre Modelle benutzt. Als loss-of-function Ansatz wurde das DEREG Mausmodell verwendet, in dem die regulatorischen T Zellen aufgrund der transgenen Expression des Diphtheriatoxin-Rezeptors mittels Gabe von Diphtheriatoxin eliminiert werden können. Als gain-of-function Ansatz wurden die regulatorischen T Zellen unter der Benützung von IL-2/anti-IL-2
6 2. Zusammenfassung 9 Immunkomplexen (IL-2ic) gezielt expandiert. Diese Experimente zeigten, dass die regulatorischen T Zellen die Funktionalität der virus-spezifischen CD8 + und CD4 + T Zellen unterdrücken und dadurch eine chronische Virusinfektion erlauben. Die Resultate identifizieren somit einen zusätzlichen Mechanismus über den IL-21 eine funktionelle Beeinträchtigung der antiviralen T Zellen und eine daraus resultierende virale Chronizität durch die Limitierung der virus-induzierten regulatorischen T Zellproliferation vorbeugt. In einem Nebenprojekt wurde die Redundanz der Zytokine IL-21 und IL-2 während einer akuten LCMV Infektion untersucht, da beide für ein optimales CD8 + T Zellgedächtnis während einer chronischen Infektion verantwortlich, aber für eine akute Infektion erlässlich sind. Die Benützung von gemischten Knochenmarkschimären erlaubte den Vergleich der Bedeutung von IL-2R, IL-21R oder beiden Zytokinrezeptoren gemeinsam auf die Aktivierung, die Funktion und die Gedächnisantwort der CD8 + T Zellen in einer akuten LCMV Infektion. Ebenfalls erlaubt es die Beantwortung der Frage, ob der fehlende Effekt während der akuten Infektion aufgrund einer gegenseitigen Kompensation von IL-2 und IL- 21 zustande kommt. Diese Analyse deutete darauf hin, dass IL-2 und IL-21 teilweise für einander kompensieren können. IL-2 und IL-21 hatten keinen Einfluss auf die Aktivierung von CD8 + T Zellen, jedoch spielten beide Zytokine eine wichtige Rolle im etablieren einer funktionellen CD8 + T Zellgedächnisantwort während einer akuten Infektion. Der zweite Teil der Arbeit hatte zum Ziel, das komplexe Signalnetzwerk des coregulatorischen Rezeptors Herpes virus entry mediator (HVEM) während einer viralen Infektion besser zu verstehen. Über Interaktionen mit Liganden, wie zum Beispiel B and T cell attenuator (BTLA) und LIGHT (lymphotoxin-like, inducible expression, competes with herpes simplex virus glycoprotein D for HVEM, a receptor expressed by T lymphocytes), kann HVEM das Ausmass und die Länge der T Zellaktivierung negativ oder positiv beeinflussen. Das Binden von LIGHT an HVEM induziert ein Signal das hauptsächlich als Förderung der pro-inflammatorischen Immunantwort beschrieben ist. Dies steht im Gegensatz zur Bindung mit BTLA, welches ein unterdrückendes Signal via HVEM liefert. Bis jetzt wurden die Interaktionen mit HVEM und deren Signale hauptsächlich in vitro untersucht und nur wenig ist über dessen Rolle während einer Infektion bekannt. Die vorliegende Arbeit zeigt einen ausführlichen Vergleich der anti-viralen T Zellantwort in HVEM-, LIGHT- und BTLAknockout Mäusen während einer LCMV Infektion. Diese Analyse zeigte, dass die vermittelten co-regulatorischen Signale durch die Interaktion mit HVEM für die T
7 10 2. Zusammenfassung Zellaktivierung, die Expansion und Gedächnisantwort in einer akuten Infektion nicht benötigt werden. Hingegen führte ein Fehlen von HVEM oder BTLA zu einer fehlenden Immunkontrolle bei der chronischen LCMV Infektion, was auf eine wichtige Rolle von HVEM und BTLA während chronischen Infektionen hinweist. Da jedoch die T Zellantwort nicht beeinträchtigt war, deutet dies auf eine potentielle Aufgabe von HVEM und BTLA in der humoralen Immunantwort hin. Eine weitere Beobachtung war, dass LIGHT knockout Mäuse eine weniger starke Kontraktion der regulatorischen T Zellpopulation aufzeigten, welche normalerweise zu Beginn der viralen Immunantwort beobachtet wird. Da die Kontraktion der regulatorischen T Zellen in HVEM knockout Mäusen nicht verändert war, muss LIGHT durch seinen anderen Bindungspartner, LTβR, ein Signal auslösen, welches zur Kontraktion der regulatorischen T Zellen beiträgt. Obwohl die Kontraktion der regulatorischen T Zellen in LIGHT knockout Mäusen verändert war, wurde keinen Einfluss auf die spätere Immunantwort gefunden, was die Bedeutung der Senkung der regulatorischen T Zellen unbeantwortet lässt. Zusammengefasst zeigen die Daten dieser Arbeit, dass die Regulation der regulatorischen T Zellen durch IL-21 für den Ausgang einer viralen Infektion essentiell ist und dass die HVEM Rezeptorinteraktionen hauptsächlich eine Rolle in der Kontrolle einer chronischen Virusinfektion spielen.
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