Experimental immunology in Zürich: The legacy of studying disease‐related Ag

Experimental Immunology in Zürich is connected to the names of Rolf Zinkernagel and Hans Hengartner, whose contributions to the field of murine anti-viral immune responses have been remarkable. With their studies and Rolf Zinkernagel's hallmark paper “Immunology taught by viruses” in Science 1, they have promoted the idea that model Ag, such as those from hen eggs, might differ significantly from disease-related Ag, especially when they are not encountered in the context of an infection or the inflammatory environment of autoimmune disease. From August 2008 on, we, Burkhard Becher and Christian Münz, will form with our laboratories the Institute of Experimental Immunology at the University Hospital Zürich, and will continue our studies on disease-related Ag in the Neuroimmunology and Viral Immunobiology sections of the institute, respectively (Fig. 1). In the tradition of Zinkernagel and Hengartner, we will study autoimmune disease and anti-viral immune control with disease-relevant Ag, but will focus primarily on human disease- and human pathogen-related Ag. Christian Münz (left) and Burkhard Becher (right) will head the Viral Immunobiology and Neuroimmunology Laboratories, respectively, at the Institute of Experimental Immunology, University of Zürich, in succession of Rolf Zinkernagel and Hans Hengartner. The Viral Immunobiology Laboratory, headed by Christian Münz, will continue its work of the past 10 years at the Rockefeller University in New York, USA, on the immune control of the persistent and oncogenic EBV. This common γ-herpesvirus infects more than 90% of the adult human population. Although it was the first human tumorvirus discovered 2, 3 and readily transforms human B cells in vitro 4, it is carried by most infected individuals asymptomatically and only rarely causes tumors such as Hodgkin's and Burkitt's lymphoma 5. This is probably due to the fact that the human immune system establishes in most cases a comprehensive immune control, and only when weakened by immunosuppressive co-infections, such as with HIV, or therapy after transplantation for example, EBV-associated malignancies emerge at increased frequencies 6, 7. The high infectious rate and tumorigenic potential of EBV have probably shaped the human immune system, which acquired during its co-evolution the capacity to control this pathogen in a life-long asymptomatic infection. Understanding and learning from EBV-specific immune responses will be the research topic of the Viral Immunobiology Laboratory at the Institute of Experimental Immunology. EBV can teach us how asymptomatic and persistent immune control can be established and maintained. Characterizing the cornerstones of EBV-specific immunity will allow us to identify deficiencies in the immune responses against less well-controlled persistent pathogens – with HIV and HCV at the top of the list – which adjuvant characteristics are needed to establish persistent immune control, and which Ag should be targeted for therapeutic intervention. Our recent research has started to provide some answers to these questions. One of the cornerstones of EBV-specific immune control is probably the CD4+ T-cell response to the nuclear antigen 1 of EBV (EBNA1). We found that all healthy EBV carriers have this immune response 8, 9, and that EBNA1-specific CD4+ T cells can target EBV-transformed B cells directly 10 and block B-cell transformation by EBV 11. Loss of this EBNA1-specific immune response from the blood circulation is associated with the development of EBV+ Hodgkin's lymphoma 12, and endemic, as well as HIV-associated Burkitt's lymphoma 13-15. While studying why the human CD4+ T-cell response to EBV focuses on EBNA1, we discovered that this Ag gains access to MHC class II presentation by an intracellular route 8. This quite unusual Ag-processing pathway requires at least in part macroautophagy 16. We and others extended this discovery by documenting that macroautophagy, a catabolic pathway for cytoplasmic constituent transport into lysosomes, delivers Ag and self-proteins quite efficiently for MHC class II presentation to CD4+ T cells 17, 18. These findings extend the usefulness of CD4+ T cells to monitoring intracellular Ag in addition to endocytosed proteins. Our studies on EBNA1 characterized an essential immune response and the targeted Ag, but did not reveal the conditions under which this probably protective response is primed. However, for efficient adjuvant design to elicit EBNA1-specific protective immune responses in EBV− individuals or patients suffering from EBV-associated malignancies, the knowledge of the priming conditions is essential. Along these lines, we have now started to document early events during the EBV-specific immune response. We could demonstrate that EBV activates blood DC 19, which then in turn are able to activate NK cells of tonsils, the primary site of EBV infection. These activated NK cells are then able to limit B-cell transformation by EBV 19 and also assist DC in the priming of Th1-polarized T-cell responses 20 that predominate EBV-specific immune control 21. This knowledge of relevant adjuvants and Ag is currently being combined for the induction of protective immune responses against EBV in a mouse model, which has been rendered susceptible to EBV infection by human immune system components' reconstitution 22. Our research in Zürich will continue the development of an in vivo model for EBV infection and EBV-specific immune control as a platform for EBV-specific vaccine testing. The Neuroimmunology Laboratory, headed by Burkhard Becher, will continue to study immune responses primarily driven by self-Ag. These studies were started at the Montreal Neurological Institute in Canada and at the Dartmouth Medical School in the USA, where we have been studying the interaction of the immune system with the CNS in the context of autoimmunity. EAE is a valuable model for human CNS inflammation, such as MS and disseminated encephalomyelopathy. While it is clear that the adaptive immune system, primarily pathogenic Th cells, invades the CNS and orchestrates debilitating tissue destruction, the precise pathogenesis and underpinnings of the inflammatory insult remain incompletely understood 23. In the past, we could demonstrate to what extent CNS-resident immune cells (i.e. microglia) contribute to the inflammatory cascade (reviewed in 24). Notably, we could determine that microglial activation, mediated by their interaction with invading T cells, initiates an inflammatory cascade that ultimately leads to overt tissue inflammation 25-27. In particular, the engagement of CD40 on microglia by its ligand CD154 (CD40L) on activated effector T cells drives the production of vasoactive substances and chemokines, which subsequently debilitate the integrity of the blood–brain barrier and the recruitment of additional leukocytes into the now vulnerable brain parenchyma 27. Microglia were also the prime candidates to present self-reactive brain-specific Th cells with their cognate Ag in the context of MHC class II molecules 23, 28, 29. However, while microglia were repeatedly shown to be capable of efficient Ag presentation in vitro, we found that this simplistic view does not hold up to scrutiny in an in vivo setting. The primary APC permitting TCR/MHC class II interactions and cognate Ag recognition by neuro-Ag-reactive Th cells are not microglia but rather rare vessel-associated DC 30, 31. Therefore, neuro-Ag-reactive T cells are permitted entry into the CNS after they have been licensed by vessel-associated DC. Subsequently, such licensed T cells can penetrate the CNS tissue and interact with resident microglia, which in turn initiate the inflammatory cascade (reviewed in 32). In addition to elucidating the critical roles of APC subsets and their activation during EAE induction, an important aspect of our studies is a better understanding of the nature of pathogenic T cells. Their emergence relies not only on the availability of self-Ag (Signal I) but also on the composition of the primary immune synapse, which forms between Th cells and APC. The signature of co-stimulatory molecules (Signal II) and the cytokine environment (Signal III) is crucial for the generation of a pathogenic T-cell repertoire (ThPath). In particular, the cytokine milieu is widely held to provide the ultimate instruction to Th cells to fully develop their autoimmune pathogenic potential 33, 34. In the past, IFN-γ-producing Th1 cells were held responsible for the autoimmune attack against the CNS. We and others could clearly demonstrate that this paradigm is far too simplistic to describe the events following the induction of EAE in mice. We were the first to report the fact that not the Th1-instructing cytokines IL-12 and IL-18 but the Th17-polarizing IL-23 is responsible for the generation of pathogenic Th cells in vivo 33, 35, 36. While the regulation of this newly described polarization pattern becomes increasingly transparent, the precise function of Th17 and/or ThPath cells (if they are the same entity) remains to be established. We will continue to specifically decipher the cytokine signature and communication, essential for the emergence of autoimmunity and thus hope to define novel and specific therapeutic targets for the treatment of autoimmune disease. In addition to the separate research endeavors of the Neuroimmunology and Viral Immunobiology sections of the Institute of Experimental Immunology, we also hope to support a synergistic research program into the role of infectious agents in the initiation and promotion of CNS autoimmunity, as well as the extent to which immune mechanisms that cause autoimmunity could be of protective value against tumors. While autoimmunity is definitely undesired, the control of malignancies represents essentially the flip side of autoimmunity and efficient anti-cancer immune surveillance is a desired form of autoimmunity. We hope to apply the findings obtained by studying autoimmune responses to aid the development of therapeutic avenues of efficient anti-cancer immunity initially in mice and hopefully subsequently in humans. In addition, there is now mounting evidence for a selective deregulation of EBV-specific immune control in MS patients, namely, individuals with symptomatic EBV infection during adolescence or adulthood have an increased risk of developing MS 37, 38, and primarily EBNA1-specific antibody titers increase several years before the clinical onset of MS 39. Accordingly, children with MS are uniformly EBV seropositive compared with 58–85% of healthy age-matched controls 40, 41. Interestingly, this deregulation of EBV-specific immune control selectively affects EBNA1-specific CD4+ T cells 42. These EBNA1-specific CD4+ T-cell responses of MS patients are broadened in their EBNA1 epitope recognition 43 and partially cross-react with myelin Ag 42]. Therefore, it is tempting to speculate that symptomatic EBV infection primes cross-reactive EBNA1-specific CD4+ T-cell responses that might augment MS development. We plan to combine the expertise of both of our laboratories in the new Institute of Experimental Immunology to characterize the similarities and differences between anti-tumor, autoreactive and virus-driven immune responses. In the tradition of Zinkernagel and Hengartner we are planning to continue to study disease-associated Ag and their recognition by the mouse and human immune systems in the context of viral infections and autoimmune disease. In collaboration with our clinical colleagues at the University Hospital of Zürich we are hoping to translate some of our findings into therapeutic strategies, in order to utilize the immune system, as evolution's answer to pathogenic challenge and disease resolution in general, more broadly in the clinic.

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