Introduction

Our immune system is tightly regulated by the cross-talk among a wide range of immune cells. These immune cells are highly dependent on external cues, such as cytokines and chemokines, which regulate their proliferation, differentiation, survival and migration. IL-2 is a common gamma c (c) cytokine that plays pivotal roles in immune homeostasis and T cell activation. IL-2 binds to two different types of receptors, namely the intermediate-affinity dimeric IL-2 receptor (IL-2R) comprised of the IL-2Rβ (CD122) and the γc (CD132) subunits; or the high-affinity trimeric IL-2R, which has an additional IL-2Rα subunit (CD25). Downstream IL-2 signaling is mediated through three main intracellular signaling pathways, namely the JAK- STAT5, the PI3K and the MAPK pathways.

Insights from the Lab

IL-2 biology and immunotherapies are the main research interest of our lab. Based on the binding signature of IL-2 to its receptors, we were able to generate different IL-2/anti-IL-2 monoclonal antibody (mAb) complexes (IL-2cx), thus biasing the activity towards immune cells expressing dimeric or trimeric IL-2Rs. For the selective stimulation of CD8+T cells and NK cells, we have generated the NARA1 mAb, which upon complexing with IL-2, directs IL-2 to cells expressing dimeric IL-2 receptors. On the other hand, a recently-developed mAb, termed UFKA-20, is able to selectively deliver IL-2 to trimeric IL-2 receptors and thereby potently expands so-called regulatory T cells. We are studying the effect of such IL-2cx formulations on different subsets of immune cells and investigate their therapeutic potential in various preclinical models of cancer and autoimmune diseases.

Another avenue of our research focuses on the characterization of intracellular signaling events downstream of the IL-2R, and specifically the role of STAT5 protein in the JAK-STAT5 pathway. We are currently developing a real-time fluorescent-based reporter assay to detect STAT5 activation in living cells. In addition to structural studies, such reporter assays could complement our understanding of STAT proteins and enable high-throughput screenings for the identification of novel compounds that can interfere with this pathway.