Figure 2:

Trans-presentation of IL-15 and IL-2

A. Because of very high affinity between IL-15Rα chain for IL-15, IL-15Rα chain can easily capture and “hold” released IL-15 for long time-periods. This IL-15Rα/IL-15 complex can be then easily trans-presented to intermediate affinity IL-2/IL-15 receptor, expressed on T cells or NK cells.

B. In contrast, CD25 (IL-2Rα chain) has only low affinity for IL-2, so it is highly unlikely that CD25 would be able to effectively capture small concentrations of IL-2 and create stable CD25/IL-2 complexes for trans-presentation, if IL-2 can easily diffuse to the environment. However, if instead the IL-2 is released into the synaptic cleft, which represent an enclosed space between peripheral supramolecular activation cluster formed by adhesion molecules such as lymphocyte function associated antigen-1 (LFA-1) and intercellular adhesion molecule-1 (ICAM-1), then its diffusion is limited and high IL-2 concentrations can be achieved. Under those circumstances, CD25 expressed on the surface of dendritic cell (DC), which formed stable immune synapse (IS) with antigen-specific T cell, can effectively capture released IL-2 and trans-present it to the T cell at the time when T cell does not yet express CD25. This cytokine signal (Signal 3), delivered concomitantly with the Signal 1, provided by T cell receptor (TCR) specifically recognizing peptide loaded on the major histocompatibility complex (MHC) and the co-stimulatory Signal 2 (e.g. provided by interaction of CD28 with CD80 or CD86) seems to be necessary for efficient activation of human T cells and their differentiation to cytokine-producing effector cells.

C. When CD25 on the DC is blocked by daclizumab, then primed T cell cannot receive IL-2 signal (Signal 3) concomitantly with its Signal 1 and 2, resulting in sub-optimal stimulation of T cell. The functional consequences are inhibition of antigen-specific T cell activation, formation of antigen-specific effector and memory T cells.