Dr. E.J.A.M. (Alice) Sijts

Dr. E.J.A.M. (Alice) Sijts

Universitair hoofddocent
030 253 2471

Research interests:

The group of Alice Sijts at the Division of Immunology of the Veterinary Faculty is interested in the basic mechanisms that lead to protective T-cell responses to both infections and tumor growth, which is of importance for rational design of novel strategies for immune intervention.

One type of immune effector cell known to play an important role in immune protection to intracellular pathogens and tumor growth is the CD8 T cell / Cytotoxic T lymphocyte (CTL). CD8 T cells recognize pathogen-derived proteins (antigens) as peptides that are presented on the cell surface by MHC class I molecules. Specific recognition of MHC-peptide complexes triggers the lytic mechanisms of CD8 T cells, resulting in elimination of the target cell.

 CD8 T cell responses triggered by infection or following vaccination are characterized by a prominent “immunodominance hierarchy”. This means that, although pathogens encode a plethora of peptides that can be presented by MHC class I molecules, only a few are “seen” by responding CD8 T cells.

MHC class I-presented peptides that are recognized by CD8 T cells are produced upon degradation of pathogen-derived, intracellular antigens by a large protease complex, the proteasome. Thus, 1) the intrinsic activity of the proteasome complex, as defined by the enzymatically active sites, 2) the binding of regulatory complexes to the proteasome, and 3) substrate targeting mechanisms play an important role in the generation of pathogen-derived MHC class I-binding peptides and the specificity of pathogen-specific CD8 T cell responses. In support of this, we have shown that the kinetics of proteasome-mediated peptide generation determine the immunodominance hierarchy of CD8 T cell responses to the intracellular bacterium Listeria monocytogenes. Conversely, we have shown also that regulation of proteasome-mediated generation of MHC class I ligands from self-proteins is important to prevent the onset of CD8 T cell mediated auto immune diseases.

CD8 T cells controlling tumor growth are often directed to a few tumor antigens that either are associated with the tumor lineage or have been modified (mutated) during tumor development. Although such T cells can prevent tumor growth, tumors often establish a tumor-intrinsic immunosuppressive environment, inactivating such tumor-specific T cells. Many studies including ours have shown that the immune regulatory mechanisms operating within tumors may be reverted, leading to CD8T cell-mediated tumor rejection.

Current research interests include:

a.     One of our aims is to improve our understanding of the molecular mechanisms underlying immune recognition and immunodominance, which will help to develop new generations of CD8 T cell memory-inducing, protective vaccines. Recent studies have shown that proteasomes not only cleave proteins into fragments, but also ligate the generated fragments, leading to the generation of “spliced” peptides. Such peptides are recognized by CD8 T cells reacting to tumor growth, as well as to infection, as recently shown by us (Platteel et al, Cell Reports 2017). We are currently investigating the role of spliced peptides in pathogen-specific, CD8 T cell-mediated immune protection, in collaboration with scientists at King's College London and the Max Planck Institute for Biophysical Chemistry, Göttingen.

b. Another important goal is to develop strategies to enhance the immunogenicity of vaccine vector-encoded antigens, so that the CD8 T cell response and CD8 T cell memory induced by vaccination will be multivalent and robust. This research is performed in collaboration with different international partners, as part of the ADITEC (advanced immunization strategies) consortium and in context of the Horizon2020-financed VacPath (novel vaccine vectors to resist pathogen challenge) project. The latter project, coordinated by us, focuses on the development of a mucosal, vectored vaccine against the intracellular bacterium Chlamydia trachomatis (cause of sexually-transmitted disease). The consortium combines unique expertise with different types of bacterial and viral vaccine vectors, with profound expertise in strategies for substrate targeting within professional antigen presenting cells, in order to optimize the processing kinetics of vector-encoded antigens. Results of this project may be translated for development of vectored vaccines against other )emerging) intracellular pathogens or cancer.

c.      A collaborative project within the immunology division involves the design and testing of nanoparticle carriers, for cytosolic delivery of drugs or vaccine antigens. This project was initiated under the IMI-funded European project COMPACT.

d. A further goal of our research is to develop novel immune intervention strategies to re-activate tumor-specific CD8 T cells. In the Horizon2020-financed project TumorTregTargeting, we collaborate with different international partners to develop novel antibody-based technologies to relieve intratumoral immune suppression.