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EBV specific CD4+ T cell responses

Epstein Barr virus establishes a life-long asymptomatic infection in more than 90% of the adult human population. Only a minority of EBV infected individuals develops EBV associated malignancies like Hodgkin's disease, Burkitt's lymphoma and nasopharyngeal carcinoma. We believe that the difference between these two courses of EBV infection lies in the EBV specific immune control that is raised in these individuals. Indeed, immunosuppression by drugs after transplantation, by genetic disorders or by HIV coinfection releases EBV from immune control and is accompanied by an increased frequency of EBV+ lymphomas.

EBV associated tumors carry latent EBV infection. All eight latent EBV antigens, however, are only expressed in tumors of immunosuppressed individuals. The spontaneously arising EBV+ tumors in contrast carry only a subset of latent EBV antigens. Indeed, the only EBV antigen expressed in all EBV associated malignancies is the Epstein-Barr virus nuclear antigen 1 (EBNA1). Therefore, EBNA1 should be the optimal target for immune therapy against these tumors and forms indeed an essential antigen for the immune control of EBV in healthy EBV carriers.

We demonstrated that CD4+ T cells in healthy EBV carriers consistently recognize EBNA1 and that these EBNA1 specific CD4+ T cells can lyse EBV+ tumor cells like Burkitt's lymphoma as well as prevent B cell transformation by EBV in vitro. Therefore, we are currently evaluating different vaccination strategies to enhance EBNA1 specific CD4+ T cell immunity, which could be of therapeutical benefit for patients with EBV associated malignancies.

CD4+ T cells recognize antigen presented on MHC class II molecules. While MHC class II processing of exogenous antigen, coming from outside the presenting cell, is well characterized, MHC class II processing of endogenous antigen, coming from inside the presenting cell, is poorly defined. We analyzed this endogenous MHC class II processing for EBNA1, and determined that macroautophagy delivers EBNA1 to the MHC class II loading compartment. Macroautophagy is a cytosolic degradation pathway, which involves sequestering cytoplasmic content by an isolation membrane, and transport of this material via autophagosomes to lysosomes for degradation. We are currently analyzing if CD4+ T cells can target other MHC class II+ tumors like epithelial cell tumors after processing of tumor antigens via the same pathway.

In addition, we will analyze if EBNA1 specific CD4+ T cell immunity selectively lacks in EBV associated malignancies like Hodgkin's lymphoma and nasopharyngeal carcinoma. A decreased EBNA1 specific CD4+ T cell response in patients with EBV associated malignancies compared to healthy EBV carriers would justify immune intervention in these tumor patients to reinstall EBNA1 specific immune control.

Related articles from our laboratory:
  1. Casper Paludan, Kara Bickham, Sarah Nikiforow, Ming L. Tsang, Kiera Goodman, Willem A. Hanekom, Jean-Francois Fonteneau, Stefan Stevaovic and Christian Münz, "EBNA1 specific CD4+ Th1 cells kill Burkitt's lymphoma cells", Journal of Immunology (2002), 169: 1593-1603.
     
  2. Sarah Nikiforow, Kim Bottomly, George Miller and Christian Münz, "Cytolytic CD4+ T cell clones reactive to EBNA1 inhibit Epstein-Barr virus induced B cell proliferation", Journal of Virology (2003), 77:12088-12104.
     
  3. Christian Münz, "Epstein Barr Virus nuclear antigen 1: from immunologically invisible to a promising T cell target", Journal of Experimental Medicine (2004), 199:1301-1304.
     
  4. Casper Paludan, Dorothee Schmid, Markus Landthaler, Martina Vockerodt, Dieter Kube, Thomas Tuschl and Christian Münz, "Endogenous MHC class II processing of a viral nuclear antigen after autophagy", Science (2005), 307: 593-6.
     
  5. Christian Münz, "Autophagy and antigen presentation", Cellular Microbiology (2006), 8: 891-898.