MHC class I and II molecules control most immune responses by presenting a fragment of an antigen to T cells. MHC class I molecules mainly present cytosolic/nuclear derived fragments whereas those for MHC class II molecules are generated in late endocytic structures. For successful immune responses, various processes have to occur including protein formation, folding and transport, protein degradation and multi-vesicular body formation. We study these processes in living cells and the goal is to establish the technology to perform biochemistry not any longer in tubes but in living cells. Therefore we combine fluorescent microscopy (FRAP, FLIM, FRET, FLIP and photoactivation) with molecular biology, compound chemistry and protein chemistry. In vivo biochemistry results in many exciting and novel insights in the processes occuring in cells and the immune system.
Neefjes is studying the molecular and cell biology of antigen processing and presentation by MHC class I and MHC class II molecules. Neefjes' team has solved many steps in our current understanding of the MHC class I and MHC class II cell biology. This work is broadly applied in modern immunotherapy approaches. He is now combining that with genetic and chemical screens to find new targets and new leads for manipulation. Neefjes' work also formed the basis of a line of translational research where chemistry (drug screens) are tested on fresh tissue materials to predict new drug active on individual patients. This has yielded new drug indications and new radiosensitizers (tested for mesothelioma and H&N cancer).
As a spin off, Neefjes has developed a number of unique lines of research with implications for cancer. These include the basis for radio-immunotherapy (now becoming popular for boosting tumor immune responses with the check-point antibodies). And it includes the description of the bacterial use of host pathways in their infection cycle, pathways that are also activated in many tumors. Neefjes showed that (genetic or chemically inhibiting) these pathways eliminated intracellular bacterial pathogens, such as Salmonella and M.tuberculosis. This has resulted in the first description of an antibiotic target in the host and allows eradication of multidrug resistant M.tuberculosis through the inhibition of host cell protein, in this case PKB/Akt.
Currently his main lines of research are:
1. A further description of how motor proteins control motility of MHC class II compartments. Neefjes was the first to describe a critical role of cholesterol and another intercellular compartment, the ER in the control of motility and fusion of endo/lysosomes and phagosomes. He now focuses on how motor proteins are switched on endosomes to further understand the complex behavior of vesicle transport (Refs. 184, 212, 220, 222, 242)
2. The molecular mechanisms of endosomal vesicle organization defined that is lost during mitosis to equally distribute these over the daughter cells. This may yield entirely new targets for mitosis control and new biology and illustrates why cells have a defined intracellular organization (Ref 197)
3. Bacterial contribution to cancer. The Neefjes team has generated the first causal relationship between bacterial infection and cancer (until now this was based on epidemiology). Neefjes has shown this for Salmonella Typhi and gallbladder carcinoma (both highly frequent in India and Pakistan) and will expand this to other bacterial and Schistosoma infections. This is a unique line of research of a largely ignored relationship. Neefjes is leader (and in many cases founder) in these fields and will aim to further explore these the coming years. (Refs 170, 238)
4. Cell biology of anti-cancer drugs. This has yielded new activities for the anthracyclin class of drugs that went unnoticed to both clinicians, scientists and patients for over three decades. Anthracyclines can remove histones from defined areas in the genome and then in fact act as epigenetic modifiers. In addition, the attenuate DNA repair. New drug resistance mechanisms and solutions have been defined. This line of research is close to reintroducing an old cancer drug with new activities into the clinic. (Refs 221, 237)
In summary, the Neefjes lab has always aimed at exploring new fields. This yielded many new concepts (peptidases, the MIIC, DRiPS, TAP etc) in the understanding of the mechanisms used by our body to activate immune cells for infections and cancer. This has become textbook knowledge and is widely applied. The study of the endosomal system for understanding MHC class II molecules yielded further understanding of the infection cycle of bacteria, yielding the first description of host cell-targeted antibiotics and the causal relationship between bacterial infections and cancer (such tumors can then be prevented through correct health measures). Next to resolving fundamental cell biological issues (why do endosomes move the way they move and why they located at a defined spot in cells?), Neefjes also introduced cell biology in the study of old drugs to define new activities with clinical implications. This illustrates that highly original approaches in cell biology can find application in an unpredicted yet highly relevant manner.
Leids Universitair Medisch Centrum
2333 ZC Leiden
Tel: +31 71 5268722
2300 RC Leiden