G Protein Coupled Receptor Kinase 3 Regulates CCR7 Signaling, Trafficking, and T Cell Responses to CCL19 and CCL21.

G protein-coupled receptors (GPCR) can bind multiple ligands leading to differential signaling events termed biased signaling. GPCR kinases (GRKs) can control the phosphorylation patterns of a GPCR to regulate biased signaling. Since the functions of GRKs are dependent on the local cellular environment, our study focused on investigating the roles of GRK3 in regulating biased and overlapping signaling events downstream of CCR7 activation by its ligands CCL19 and CCL21 in T cells, where CCR7 is expressed endogenously. We found stable CCR7 internalization, Gαi3 activation, and β-arrestin recruitment were regulated by GRK3 downstream of CCL19 activation of CCR7. In contrast, while CCL21 does not promote recruitment of β-arrestins, GRK3 had no effect on internalization of CCL21 bound CCR7, or its ability to activate Gαi1, Gαi2 or Gαi3. We also found that GRK3 limited T cell migration and Ca2+ mobilization in response to both CCL19 and CCL21. Since mis-regulation of CCR7 and its ligands have been linked to autoimmune disease, these studies could lead to a better understanding of mechanisms that promote homeostasis or pathogenesis.