- Dr Irma Joosten, Principal Investigator
- Dr Hans Koenen, Co-Investigator
- Prof. J. Han van Krieken, Research Associate
- Dr Luuk B. Hilbrands, Research Associate
- Prof. Peter C. van de Kerkhof, Research Associate
- Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
- Effect of Regulatory T Cell Diversity on the Immune Response
It has recently become clear that a particular population of T cells, the immunosuppressive regulatory T cells (Treg; as opposed to aggressive effector T cells) is crucial in the induction and maintenance of immunological tolerance. In transplantation, the balance between Treg and aggressive effector T cells is important for the eventual outcome; too few Treg numbers will result in transplant rejection. This knowledge can be exploited for the development of new therapeutic designs involving the infusion of substantial numbers of ex vivo-expanded autologous Treg. In mouse models, this type of therapy, whereby the cells were re-infused together with the transplanted organ, already successfully prevented graft rejection. Clinical trials with ex vivo-expanded cells have been initiated. This treatment can only be successful if sufficient numbers of highly potent suppressors can be obtained. We have now developed an expansion technique that enables us to do this. Quite unexpectedly, we noticed that upon expansion, two different types of Treg subsets emerged. These subsets had distinct phenotypes and suppressive capacity. For successful therapeutic application of Treg we feel that it is imperative to study these subsets in more detail, to understand their behavior in relation to effector cells and notably, to each other. The observed reciprocal expression of a particular receptor – ligand pair (CD27–CD70) indicates that such an interaction might occur. Also we may learn whether the diversity may have any possible clinical implications.
Our objectives are twofold. 1. The two human Treg subsets will be studied under laboratory conditions to analyze if there is a developmental relationship between the subsets, and how they interact. The cells will be characterized in detail, with particular focus on the CD27–CD70 signaling pathway. 2. Since Treg might behave differently under laboratory conditions than in the patient, we need to study how the cells behave in vivo. Therefore, we will analyze the actions of Treg subsets in a mouse model. We will again analyze a putative developmental relationship, if they cooperate functionally, where they are localized upon infusion and how long they survive. Together these experiments will teach us more about the biological features of Treg and will enable optimal Treg selection for Treg-based therapy.