Comment on “CXCL9 Causes Heterologous Desensitization of CXCL12-Mediated Memory T Lymphocyte Activation”

We read with interest the recent study by Giegold and colleagues (1) reporting that the CXCR3 ligand CXCL9 is able to desensitize the response of memory T cells to the CXCR4 ligand CXCL12. As the authors suggest, heterologous chemokine receptor regulation represents a powerful regulatory mechanism for the control of inflammation. Using a previously described mimetic of CXCL10 (2, 3), another CXCR3 ligand, we demonstrated cross-regulation of CXCR4 and CCR5 in vitro and in vivo (4). The work of Giegold et al. (1) complements our study as although the three ligands of CXCR3 (CXCL9, CXCL10 and CXCL11) are able to elicit T cell migration, recent studies have suggested that these are allosteric ligands that elicit ligand-specific responses (5), which represent an additional level of potential regulation (6). Having described the internalization of CXCR4 and CCR5 upon CXCR3 ligation, we explored the mechanism underlying this and observed a chemokine receptor heterodimer of CXCR3 and CCR5 on the surface of T cells and demonstrated a PKC-dependent cross-phosphorylation of CCR5 by the CXCR3 ligand. Based on our study and the work of Giegold et al. (1), we therefore suggest that CXCR3 may also form a heterodimer while allowing similar cross-phosphorylation of CXCR4. This would suggest a mechanistic explanation for their observations of a loss of surface receptor and consequent chemokine responsiveness.