Complex roles of the CXCR3 chemokines in immune-mediated neurological disease (96.1)

Abstract The chemokine receptor CXCR3 binds CXCL9, CXCL10 and CXCL11 and promotes the trafficking of activated T-cells. Although these chemokines are highly elevated in the CNS in MS and the animal model, experimental autoimmune encephalomyelitis (EAE), their role is unknown. Here we show that while IFN-γ is the principal mediator of CXCR3 ligand gene expression in the CNS in EAE, the cellular localization of the individual chemokine genes is divergent suggesting functional specialisation of the CXCR3 ligand chemokines. Transgenic mice (GF-) were generated with astrocyte-production of CXCL9, CXCL10 or CXCL11. These mice do not develop neurological disease. In GF-CXCL10 and -CXCL11 mice, modest non-reactive leukocytic infiltrates were seen in the CNS. Thus, these chemokines when produced chronically are a poor stimulus for the CNS recruitment and activation of T-cells. The role of CXCR3 signaling in MOG-induced EAE was examined in CXCR3 KO mice and in GF-CXCL9, -CXCL10 or -CXCL11 mice. CXCR3 KO, GF-CXCL9 and -CXCL11 mice had more severe EAE with widely disseminated demyelinating lesions throughout the CNS. In CXCR3 KO mice with EAE the number of suppressor Treg cells in the brain was reduced. Thus, in EAE, CXCR3 chemokine ligands:have non-redundant functions,are not involved in the initial recruitment of effector T-cells to the CNS, andretain T-cells to the perivascular space and foster Treg cell interactions thereby limiting lesion spread and tissue destruction. Support: NIH NS044905.