Our research addresses the question how lymphocytes decide between living and dying. This interest originates from the work on structure and function of antigen receptors, which started with my PhD research and has been the focus of my group for many years. Lymphocytes are our favorite cells, for two reasons: 1) They are central in disease control and can be studied in vitro as well as in fully physiological settings in vivo. 2) Due to their dramatic proliferative capacity, lymphocytes live on the edge between life and death. Many different pro- and anti-apoptotic mechanisms operate within these cells, depending on their activation and differentiation stages.
Our work is in the first place inspired by the desire to improve immunotherapy of cancer. Sustaining survival of activated lymphocytes is expected to improve anti-tumor immunity. At the same time, mechanisms we elucidate may be exploited to block undesired immune responses, as in auto-immunity and transplant rejection. One main research line is therefore concerned with the role of anti-apoptotic TNF receptor family members in control of the T cell response. This work is carried out in vivo in mouse models and in matching cellular systems in vitro, whereby we presently focus on interactions between T cells and dendritic cells. In research line, we collaborate with pharmaceutical industry to validate therapeutic antibodies and recombinant proteins.
The second aim of our work is to contribute to the design of novel anti-cancer therapies by exploiting apoptotic pathways. To this end, a second main research line focuses on pro-apoptotic signaling by TNF receptor family members and DNA damaging anti-cancer regimens. This work is done for a large part in tumor cell models in vitro, using biochemical and cell biological approaches. The link between basic cell biology and clinical practice is made by studies in mouse tumor models. In this translational work, we closely collaborate with the Division of Radiotherapy.
Jannie Borst obtained a Master in Biology with Chemistry at Leiden University in 1980. She did the major part of her PhD work over the next three years at the Dana-Farber Cancer Institute, Harvard Medical School in Boston, under supervision of biochemist prof. Cox P. Terhorst. She came back to The Netherlands to work with immunologists dr. Jan E. de Vries and dr. Hergen Spits and obtained her Ph.D. degree from Leiden University in 1985. In 1987, she started her independent career with the aid of a 5-year personal fellowship from The Netherlands Organization for Scientific Research. In 1992, she obtained a staff scientist position at the NKI-AVL and in 2002 she became the head of the Division of Immunology. In 1999, she was appointed professor (bijzonder hoogleraar) in Experimental Oncology at the University of Amsterdam. In October 2008, Jannie Borst and NKI staff technician Evert de Vries celebrated the 25th anniversary of their collaboration, which forms the foundation of this research group.
● Discovery of the CD3 gamma, delta and epsilon subunits of the human T cell receptor/CD3 complex.
● Discovery of a novel human T cell subset expressing T cell receptor gamma/delta. Collaboration with other groups allowed us to identify T cell receptor gamma/delta by biochemical means. Independent work led to the generation and diagnostic use of the first antibody that could identify cells expressing T cell receptor gamma/delta in human blood and tissues.
● Discovery of the signal transduction complex associated with human membrane immunoglobulin, alias the B cell antigen receptor (BCR, a term coined by our group).
● Implication of various signaling molecules in the BCR pathway, including Btk, c-Cbl and its mechanism of action.
● Identification of TNF receptor family member CD27 and its ligand CD70 as an important T cell costimulatory system, critical for the generation of effector and memory T cells.
● Elucidation of the mechanism underlying ceramide production in response to apoptotic stimuli.
● Discovery of a novel mechanism of ubiquitination that regulates apoptosis signaling by death receptors.
Peperzak V, Xiao Y, Veraar EAM and Borst J. (2010) CD27 sustains survival of CTL in virus-infected non-lymphoid tissue in mice by inducing autocrine IL-2 production. J Clin Invest 120: 168-178.
Keller AM, Xiao Y, Peperzak V, Naik SH, Borst J. (2009) Costimulatory ligand CD70 allows induction of CD8+ T-cell immunity by immature dendritic cells in a vaccination setting. Blood 113: 5167-5175.
Middendorp S, Xiao Y, Song J.-Y, Peperzak V, Krijger P, Jacobs H, Borst J. (2009) Mice deficient for CD137 ligand are predisposed to develop germinal center-derived B cell lymphoma. Blood 114: 2280-2289.
Keller AM, Schildknecht A, Xiao Y, van den Broek M and Borst J. (2008) Deliberate expression of CD70 on steady state dendritic cells breaks CD8+ T cell tolerance and permits effective immunity. Immunity 29: 334-346.
Xiao Y*, Peperzak V*, Keller AM and Borst J. (2008) CD27 instructs CD4+ T cells to provide help for the memory CD8+ T cell response after protein immunization. J Immunol 181: 1071-1082. *equal contribution.
Keller AM, Groothuis TA, Veraar EAM, Marsman M, Mailette de Buy Wenniger L, Janssen H, Neefjes J and Borst J. (2007) Costimulatory ligand CD70 is delivered to the immunological synapse by shared intracellular trafficking with MHC class II. Proc Natl Acad Sci USA 104: 5989-5994.
Verbrugge I, Maas C, Heijkoop M, Verheij M and Borst J. (2010) Radiation and anti-cancer drugs can facilitate mitochondrial bypass by CD95/Fas via c-FLIP downregulation. Cell Death & Differ 17: 551-561.
Verbrugge I, Wissink EHJ, Rooswinkel RW, Jongsma J, Beltraminelli N, Dupuis M, Borst J, Verheij, M. (2009) Combining radiotherapy with APO010 in cancer treatment. Clin Cancer Res 15: 2031-2038.
Verbrugge I, De Vries E, Tait SWG, Wissink EHJ, Walczak H, Verheij M and Borst J. (2008) Ionizing radiation modulates the TRAIL death inducing signaling complex, allowing bypass of the mitochondrial apoptosis pathway. Oncogene 27: 574-584.
Tait SWG, de Vries E, Maas Ch, Keller A, D'Santos C and Borst J. (2007) Apoptosis induction by Bid requires unconventional ubiquitination and degradation of its N-terminal fragment. J Cell Biol 179: 1453-1466.
For additional publications, search PubMed with “Borst J” and a second key word, such as “lymphocyte”, “CD27” or “apoptosis”
Evert de Vries, technician
Gerda van der Horst, technician
Yanling Xiao, post-doc
Jonathan Coquet, post-doc
Ulf Geumann, post-doc
Chiel Maas, graduate student
Elise Veraar, graduate student
Rogier Rooswinkel, graduate student
Bert van der Kooij, graduate student