A major event for the Division of Molecular Immunology in 2008 was the recruitment of two superb immunologists from San Diego—Drs. Edith Janssen and Kasper Hoebe.
The research program of Dr. Janssen focuses on mechanistic analysis and translational exploitation of novel pathway of activation of antigen-specific adaptive immune responses discovered by Dr. Janssen involving a novel class of dendritic cells (DC) and directed towards detection of antigens expressed by apoptotic cells. Sensing and clearance of apoptotic cells has generally been considered to be a non-inflammatory or even tolerizing process. While cellular antigens are a major source for antigen cross-presentation, a process in which DC capture antigens from another source and process these captured exogenous antigens into the MHC class I pathway, the prevailing view has been that the apoptotic cells generated by normal tissue turnover are captured by DC that migrate to local lymph nodes and induce T cell tolerance, anergy or deletion. Although this is an extremely useful mechanism for preventing the development of autoimmune responses, it also inhibits the induction of protective anti-tumor responses. Seminal studies by Dr. Janssen suggest that the phagocytosis of apoptotic cells by DC can also have pro-inflammatory effects that can lead to the induction of CD4+ and CD8+ T cells specific for cell-associated antigens. This balance between immune-suppressive and pro-inflammatory responses is greatly affected by the type of DC that is involved in the uptake of apoptotic cells, and the milieu that these DC subsequently create. The Janssen laboratory aims to define the molecular and cellular mechanisms in DCs that balance the pro- and anti-inflammatory immune response to self after cell death in order to facilitate translational exploitation of these mechanistic insights in the development of effective therapeutic and preventive cancer vaccines.
The research program of Dr. Hoebe is focused on developing a thorough mechanistic understanding of the connections between innate and adaptive immunity, something essential for the generation of efficient adjuvants for vaccine development. Our understanding of how adjuvants work is limited. Fundamental questions as to what pathways drive robust T and B cell responses remain largely unanswered. In addition, there is still an urgent need to find robust, safe adjuvant pathways that will lead to strong antigen-specific immune responses. The Hoebe laboratory has recently identified an “endogenous adjuvant” pathway mediated by NK cells. NK cells detect and kill pathogen-infected host cells, as well as neoplastic cells and tissue allografts. However, studies from the Hoebe laboratory have shown that they discharge another duty as well: one that establishes a strong tie between NK cells and the adaptive immune system. Of key importance in this pathway is the recognition and killing of antigen-expressing target cells by NK cells. Subsequently, NK cell-induced cell death is recognized by dendritic cells (DC), leading to antigen cross-presentation and to strong cellular and humoral immune responses. Dr. Hoebe’s laboratory is focused on obtaining a detailed understanding of the molecular requirements of this pathway by a forward genetic approach. After N-ethyl-N-nitrosourea (ENU)-mediated random germline mutagenesis, his research team is screening for mice carrying recessive phenotypic changes in NK cell function or NK cell-driven adaptive immune responses. In his hands, ENU mutagenesis has proven to be a powerful means of identifying genes with non-redundant function in innate and/or adaptive immunity—providing new insight into genes causing severe primary immunodeficiency disorders. The approach is particularly powerful in that it is unbiased: one only needs to find phenotypes, and then establish causality by positional cloning. Dr. Hoebe is convinced that the availability of the complete mouse genomic sequence, combined with the “state of the art” technology at CCHMC—including the latest high throughput sequencing technology—will tremendously accelerate the identification of single base-pair changes responsible for observed phenotypes, making the approach now more exciting than ever. Ultimately, Dr. Hoebe’s laboratory aims to exploit the knowledge obtained on NK cell-driven adaptive immune responses for the generation of new, safer vaccine approaches. To this end Dr. Hoebe has recently started collaborating with the International Aids Vaccine Initiative to construct DNA vectors to drive activation of a variety of innate immune effectors—including NK cells.
