The general aim of our research is three-fold: The development of novel technologies for the detection and manipulation of T cell immunity, the subsequent use of these tools to provide a better insight into virus- and tumor-specific immunity, and the improvement of T cell immunity where desirable.
MHC Multimers & Cellular Barcoding
The ability to visualize antigen-specific T cell immunity and to determine the differentiation pathways and functional capacities of different subsets of T cells is essential for our understanding of pathogen- and vaccine-induced immunity.
In prior projects we have generated MHC class I and MHC class II tetramers for mice and men and have used (and are still using) these tools to visualize tumor and virus-specific CD4+ and CD8+ T cell immunity. MHC tetramer technology makes it possible to follow the development of T cell immunity at the T cell population level. However, it doesn’t allow the analysis of cell fate and cellular differentiation pathways in T cell immunity.
In a more recent project we have therefore begun to develop an approach in which individual T cells are tagged with a genetic barcode. This tagging of individual cells with unique identifiers coupled to a micro array-based detection system should allow the analysis of ‘kinship’ between the progeny of such cell populations. We expect that the development of this type of technology will prove extremely valuable in the analysis of fundamental aspects of T memory cell maintenance and cell fate analysis within the T cell lineage. In addition to its use in the analysis of fundamental aspects of T cell immunity, this approach should prove valuable for cell fate analysis in a variety of other cellular systems.
Induction and Maintenance of Tumor- and Virus-Specific T cell Immunity
Circulation of naïve CD8+ T cells is confined to peripheral blood and the secondary lymphoid organs. When virus-infected or tumor cells are present in secondary lymphoid organs, these cells can directly activate naïve CD8+ T cells through presentation of endogenously produced MHC class I-restricted antigens. However, how is the T cell immune system alerted to (the majority of) tumors that grow in peripheral organs?
Prior research from our group and from other groups has indicated that uptake and subsequent ‘cross-presentation’ of tumor-derived material by professional antigen-presenting cells (dendritic cells) forms a prime pathway for T cell activation. Although the in vivo relevance of this pathway is now well established, the cell biology of the cross-presentation pathway is only poorly understood. In the coming years we aim to tackle this issue using a combination of in vivo and in vitro systems. We have developed an experimental system that allows us to detect antigen processing intermediates formed in the process of in vitro cross-presentation and we will use this technology to analyze the subcellular pathway that is followed by exogenously-derived antigens. In parallel we are visualizing the antigen requirements for in vivo T cell priming through cross-presentation, using MHC tetramer technology. Collectively, the data obtained from this research line should be useful to provide a better understanding of the processing pathway of exogenously acquired antigens and to reveal which classes of (tumor)antigens form optimal substrates for T cell induction.
Tumor-Specific Immunity through Adoptive Therapy
In the past years our group has pioneered the retroviral introduction of antigen-specific T cell receptors into peripheral T cells as a means to induce virus- and tumor-specific immunity in vivo. Furthermore, we have developed an in vitro selection technology that allows the selection of T cell receptors with a useful specificity from libraries of T cell receptors. Collectively, these technologies provide the platform for the development of TCR gene transfer as a putative immunotherapeutic strategy. In the coming years we intend to examine a number of aspects that form the basis of this experimental therapy: In a set of immunologically-oriented studies we will determine the contribution and stability of CD4+ and CD8+ T cell immunity induced in this manner and we will determine the value of TCR gene transfer in spontaneous tumor models that more closely mimic the human situation. This line of research should prove valuable not only to assess the possibilities and limitations of this novel immunotherapeutic strategy, but also to provide novel insights into the requirements for TCR function within the peripheral T cell pool
Toebes M, Coccoris M, Bins A, Rodenko B, Gomez R, Nieuwkoop NJ, van de Kasteele W, Rimmelzwaan GF, Haanen JB, Ovaa H, Schumacher TN. Design and use of conditional MHC class I ligands. Nat Med. 2006; 12(2):246-51.
More publications by Ton Schumacher on PubMed
Ton Schumacher performed his Ph.D. research from 1988-1992 at The Netherlands Cancer Institute where he studied the interactions of MHC class I molecules with antigenic peptides in the laboratory of Hidde Ploegh. After a brief stint as a post-doc in the laboratory of Hidde Ploegh at the Massachusetts Institute of Technology, he joined the group of Peter Kim at the Whitehead Institute in Cambridge, USA in 1994. During this post-doctoral training he developed a novel screening technology for biological libraries. He joined the Netherlands Cancer Institute as an Assistant Member in 1996 to study the development of T cell immunity through biotechnological approaches. Ton Schumacher is currently Full Member of the Netherlands Cancer Institute and is recipient of a Pioneer Award.
Naik, Shalin PhD Postdoctoral Fellow
Reker Hadrup, Sine PhD Postdoctoral Fellow
Schotte, Remko PhD Postdoctoral Fellow
Bakker, Arne MSc Graduate Student
De Witte, Moniek MD Graduate Student
Gerlach, Carmen MSc Graduate Student
Van Heijst, Jeroen MSc Graduate Student
Swart, Erwin Research Assistant
Toebes, Mireille Research Assistant
Urbanus, Jos Research Assistant
Van den Boom, Marly Research Assistant