Antigen presentation and costimulation
Group leader: Robbert Spaapen PhD
Several diseases may benefit from either weakening or strengthening immune activation, often specifically in certain subsets of immune cells. Manipulation of immune responses, in particular the earliest event of antigen presentation and costimulation by antigen presenting cells, is the main focus of the Spaapen lab.
Marlieke Jongsma (technician)
Hoai-Linh Nguyen (undergraduate student)
Ann-Charlott Schneider (undergraduate student)
T cells are immune cells educated by professional antigen presenting cells (called dendritic cells) to be able to respond to whatever is abnormal in the human body (ranging from infections to cancer). T cells have a cell surface receptor recognizing a peptide presented by MHC class I or class II molecules on the cell surface of other cells. Next to this peptide-specific signal, T cells also receive costimulatory stimulation through a set of other receptors on its cell surface. To alter the T cell response, we are trying to discover mechanisms, targets and tools suitable for manipulation of the peptide antigen presentation and costimulation. We do this in the following projects:
Using a cDNA expression library for secreted proteins, we are searching for soluble factors capable of altering the MHC antigen presentation and costimulation on dendritic cells and B cells. Changes in MHC antigen presentation may effect the T cell education process in a positive or negative way, which will be tested in co-culture and translational assays. Secondly, we are trying to understand the mechanisms through which the hits from the screen are altering antigen presentation and costimulation. An elementary starting point for defining novel pathways of immune activation and inhibition.
Identification of the tight regulation of MHC class I antigen presentation
Antigen presentation by MHC class I molecules is tightly controlled, and many components of this pathway are currently known. Although many people assume that by now every component controlling antigen presentation by MHC class I molecules is known, a proper genome-wide screen to identify all essential regulators was never performed. We exploited haploid genetic screening to identify new proteins involved in the MHC class I antigen presentation pathway. Many known key proteins popped up in the hitlist, but also potentially novel regulators that were validated using siRNA knockdown in different cell lines.
This valuable set of novel critical components of the MHC-I antigen presentation pathway will be subjected to various validation and functional experiments using the latest state-of-the-art genome-editing technology and co-culture assays.
Chemical compound screening
We are searching for chemical compounds capable of altering the MHC antigen presentation and/or costimulation on antigen presenting cells. Therefore we started screening B cells using a chemical compound library (in collaboration with Huib Ovaa, NKI Amsterdam). The hits are being validated and subsequently we will perform similar strategies as for secreted proteins to determine the potential clinical impact of the compounds. Furthermore we are trying to find the targetproteins of the compounds to understand why antigen presentation and/or costimulation are altered.
Minor histocompatibility antigens
In collaboration with the group of Tuna Mutis (UMC Utrecht), we study specific immune responses after stem cell transplantation to treat leukemia. The donor T cells present in a stem cell transplant fiercely and often fatally respond to the patient’s cells (organs and tumor), despite the fact that donor and patient were MHC-matched on forehand. The only differences between donor and patient are peptides derived from polymorphic proteins presented by the MHC molecules (minor histocompatibility antigens). We developed a super-efficient method to identify the sequence of these peptides using genetic analyses, and successfully applied it a number of times in order to understand the anti-organ reaction, but also the anti-tumor response. Two of these identified peptides have immuntherapeutic value since they are only presented by tumor cells. Therefore we are improving the antigenicity of these specific peptides with chemical modifications in close collaboration with the group of Huib Ovaa (NKI Amsterdam).
Spranger S*, Spaapen RM*, Zha Y, Williams J, Meng Y, Gajewski TF. Upregulation of PD-L1, IDO and Tregs in the melanoma tumor microenvironment is driven by CD8+ T cells. Sci Transl Med 2013; 5(200):200ra116.* [These authors contributed equally to this work]
Spaapen RM, Lokhorst HM, van den Oudenalder K, Otterud BE, Dolstra H, Leppert MF, Minnema MC, Bloem AC, Mutis T. Toward targeting B cell cancers with CD4+ CTLs: identification of a CD19-encoded minor histocompatibility antigen using a novel genome-wide analysis. J Exp Med 2008; 205(12): 2863-72.