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Division of Immunology / Department of Infectious Diseases and Immunology

Tuesday 16 October 2012

Dr. Alice Sijts
Department of Immunology / Infectious Diseases, University Utrecht

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 infections, which is of importance for rational vaccine design.
One type of immune effector cell known to play an important role in immune protection to intracellular pathogens 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. 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.

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 (ref. 8). 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 (ref 10).

Current research interests include:

A.One 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 includes strategies for substrate targeting to proteasomes in professional antigen presenting cells, in order to modify the processing kinetics of vector-encoded antigens. This project is performed in collaboration with different international partners, as part of the EU FP7-financed ADITEC (advanced immunization strategies) consortium.

B. Proteasomes are barrel-shaped particles that consist of four stacked rings of seven subunits each. The catalytic activity of proteasomes is exerted by three subunits that are located in the inner two rings. Inflammatory cytokines induce the transcription of three facultative catalytic proteasome subunits that replace the constitutively expressed ones in the cellular proteasome population. Proteasomes containing these facultative subunits are named immunoproteasomes. We have found that in the absence of immunoproteasome formation, under inflammatory conditions, autoreactive CD8 T cells can expand (ref. 10). We are currently investigating the underlying mechanism, i.e. how immunoproteasome formation prevents autoreactive CD8 T cell responses.

C. In the past, we have found that the inhibitory proteasome regulator PI31 diminishes immunoproteasome formation and downregulates antigenic peptide presentation (ref. 12). A further aim is to determine the regulation and possibly additional intracellular functions of this protein.

D. 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. We are currently investigating the role of spliced peptides in pathogen-specific, CD8 T cell-mediated immune protection, in collaboration with the Institute of Biochemistry, Charité Crossover, in Berlin.

E. A collaborative project within the immunology division involves methods for cytosolic delivery of drug delivery-system packaged antigens. This project is performed in context of an IMI-funded European project.

Current group members:
Alice Sijts (UHD)
Anouk Platteel (aio)
Marit de Groot (aio)
Cornelis Bekker (Technician)
Sharesta Koenkhoen (student)

Key papers:

Zaiss, D.M., van Loosdregt J., Gorlani A., Bekker CJ., Gröne A., Sibilia M., van Bergen en Henegouwen PM., Roovers RC, Coffer PJ, Sijts, A.J. (2012) Unexpected role of the EGF-R in regulatory T-cell mediated immune regulation. Immunity (in press)

Amidi, M., van Helden, M.J., Tabataei, N.R., de Goede, A.L., Schouten, M., de Bot, V., Lanzi, A., Gruters, R.A., Rimmelzwaan, G.F., Sijts, A.J., Mastrobattista E. (2012) Induction of humoral and cellular immune responses by antigen-expressing immunostimulatory liposomes. J. Control Release. (in press)

van Helden, M.J.G., van Kooten, P.J.S., Topham, D.J., Easton, A.J., Boog, C.J.P., Busch, D.H., Zaiss, D.M.W., and Sijts, A.J.A.M. (2012) Pre-existing antigen-specific CD8+ T-cells provide protection against pneumovirus-induced disease in mice. Vaccine. 2012 Oct 5;30(45):6382-8.

Sijts, A.J., and van Eden W. (2012) The Tricky Balancing Act of using Heat Shock Proteins for Cross-Presentation. Front. Immunol. 3:114. Epub

Reemers, S. S. N., van Haarlem, D. A., Sijts, A.J.A.M., Vervelde, L. and Jansen, C. A. (2012) Identification of novel avian influenza specific CD8+ T-cell epitopes. PLoS One 7(2):e31953..

Van Helden, M.J.G., de Graaf, N., Bekker, C.P.J., Boog, C.J.P. Zaiss, D.M.W., and Sijts, A.J.A.M. (2011) Immunoproteasome-Deficiency Has No Effects on NK Cell Education, But Confers Lymphocytes Into Targets for NK cells In Infected Wild-Type Mice. PLoS One. 6:e23769

Sijts, E. J., and Kloetzel P-M. (2011) The role of the proteasome in the generation of MHC class I ligands and immune responses. Cell Mol Life Sci.68:1491.

Zaiss, D. M., Bekker, C. P., Gröne, A., Lie, B. A., and Sijts, A. J. (2011) Proteasome Immunosubunits Protect against the Development of CD8 T Cell-Mediated Autoimmune Diseases. J Immunol. 187: 2302.

de Graaf, N., van Helden, M .J., Textoris-Taube, K., Chiba, T., Topham, D. J., Kloetzel, P-M., Zaiss, D. M., and Sijts, A. J. (2011) PA28 and the proteasome immunosubunits play a central and independent role in the production of MHC class I-binding peptides in vivo. Eur J Immunol. 41:926.

Deol, P., Zaiss, D. M., Monaco, J. J., and Sijts, A. J. (2007). Rates of processing determine the immunogenicity of immunoproteasome-generated epitopes. J. Immunol. 178:7557.

Seifert U., Liermann, H., Racanelli, V., Halenius, A., Wiese, M., Wedemeyer, H., Ruppert, T., Rispeter, K., Henklein, P., Sijts, A., Hengel, H., Kloetzel, P-M., and Rehermann, B. (2004). Hepatitis C Virus Mutation Affects Proteasomal Epitope Processing in vitro and in vivo. J. Clin. Invest. 114:250.

Zaiss, D. M. W., Standera, S., Kloetzel P-M., and Sijts, A. J. A. M. (2002). PI31 is a modulator of proteasome formation and antigen processing.
Proc. Natl. Acad. Sci. USA 99:14344

Sijts, A., Ruppert, T., Rehermann, B., Schmidt, M., Koszinowski, U., and Kloetzel, P.-M. (2000). Efficient generation of a Hepatitis B virus CTL epitope requires the structural features of immunoproteasomes.
J. Exp. Med. 191:503

Sijts, A. J. A. M., and Pamer, E. G. (1997). Enhanced intracellular dissociation of Major Histocompatibility Complex class I-associated peptides: A mechanism for optimizing the spectrum of cell surface presented cytotoxic T lymphocyte epitopes. J. Exp. Med. 185:1403.