T cell receptor signaling defines the fate and pathway of ICOS internalization.

The role of the inducible costimulatory of T cells (ICOS) has been shown to be important for many different T cell outcomes and is indispensable for follicular helper T cell (T) responses. Since its discovery, there have been several studies on the regulation of ICOS at a transcriptional level. However, the post-translational regulation of ICOS has not been well characterized. Here, we demonstrate that ICOS is internalized following ligation. We show that costimulation with CD3 results in differential internalization and fate than stimulation of ICOS alone. Additionally, we show that ICOS internalization is PI3K and clathrin mediated. The studies presented here not only increase the mechanistic understanding of ICOS post-translational regulation but also give insight into the potential mechanisms by which T cells expressing high affinity receptors may be preferentially chosen to become T cells with increased ICOS levels.