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 have determined that this novel intracellular antigen processing pathway for MHC class II presentation to CD4+ T cells is active in a variety of human cells with importance to the immune system, and are currently investigating its regulation.
In addition, we have analyzed if EBNA1 specific CD4+ T cell immunity selectively lacks in EBV associated malignancies like Hodgkin’s lymphoma and Burkitt’s. We found decreasd EBNA1 specific CD4+ T cell responses in these patient populations with EBV associated malignancies and are currently developing vaccine candidates that could correct this deficiency.
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. 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
3. Dorothee Schmid, Marc Pypaert and Christian Münz
MHC class II loading compartments continuously receive input from autophagosomes. Immunity (2007), 26:79-92
4. Cagan Gurer, Till Strowig, Fabienne Brilot, Maggi Pack, Christine Trumpfheller, Frida Arrey, Chae Gyu Park, Ralph M. Steinman and Christian Münz
Targeting the nuclear antigen 1 of Epstein Barr virus to the human endocytic receptor DEC-205 stimulates protective T cell responses. Blood (2008), 112(4):1231-9
5. Christian Münz
Enhancing immunity through autophagy. Annual Review of Immunology (2009), in press.