Characterization of Receptor-Associated Protein Complex Assembly in Interleukin (IL)-2- and IL-15-Activated T‑Cell Lines

It
remains a paradox that IL-2 and IL-15 can differentially modulate
the immune response using the same signaling receptors. We have previously
dissected the phosphotyrosine-driven signaling cascades triggered
by both cytokines in Kit225 T-cells, unveiling subtle differences
that may contribute to their functional dichotomy. In this study,
we aimed to decipher the receptor complex assembly in IL-2- and IL-15-activated
T-lymphocytes that is highly orchestrated by site-specific phosphorylation
events. Comparing the cytokine-induced interactome of the interleukin
receptor beta and gamma subunits shared by the two cytokines, we defined
the components of the early IL-2 and IL-15 receptor-associated complex
discovering novel constituents. Additionally, phosphopeptide-directed
analysis allowed us to detect several cytokine-dependent and -independent
phosphorylation events within the activated receptor complex including
novel phosphorylated sites located in the cytoplasmic region of IL-2
receptor β subunit (IL-2Rβ). We proved that the distinct
phosphorylations induced by the cytokines serve for recruiting different
types of effectors to the initial receptor/ligand complex. Overall,
our study sheds new light into the initial molecular events triggered
by IL-2 and IL-15 and constitutes a further step toward a better understanding
of the early signaling aspects of the two closely related cytokines
in T-lymphocytes.