CXCR3 Signaling Reduces the Severity of Experimental Autoimmune Encephalomyelitis by Controlling the Parenchymal Distribution of Effector and Regulatory T Cells in the Central Nervous System

Abstract

The chemokine receptor CXCR3 promotes the trafficking of activated T and NK cells in response to three ligands, CXCL9, CXCL10, and CXCL11. Although these chemokines are produced in the CNS in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE), their role in the pathogenesis of CNS autoimmunity is unresolved. We examined the function of CXCR3 signaling in EAE using mice that were deficient for CXCR3 (CXCR3−/−). The time to onset and peak disease severity were similar for CXCR3−/− and wild-type (WT) animals; however, CXCR3−/− mice had more severe chronic disease with increased demyelination and axonal damage. The inflammatory lesions in WT mice consisted of well-demarcated perivascular mononuclear cell infiltrates, mainly in the spinal cord and cerebellum. In CXCR3−/− mice, these lesions were more widespread throughout the CNS and were diffused and poorly organized, with T cells and highly activated microglia/macrophages scattered throughout the white matter. Although the number of CD4+ and CD8+ T cells infiltrating the CNS were similar in CXCR3−/− and WT mice, Foxp3+ regulatory T cells were significantly reduced in number and dispersed in CXCR3−/− mice. The expression of various chemokine and cytokine genes in the CNS was similar in CXCR3−/− and WT mice. The genes for the CXCR3 ligands were expressed predominantly in and/or immediately surrounding the mononuclear cell infiltrates. We conclude that in EAE, CXCR3 signaling constrains T cells to the perivascular space in the CNS and augments regulatory T cell recruitment and effector T cell interaction, thus limiting autoimmune-mediated tissue damage.

Neuroprotection and Remyelination after Autoimmune Demyelination in Mice that Inducibly Overexpress CXCL1

“…Studies using CXCR3-deficient mice have demonstrated that CXC10/CXCR3 interactions reduce the severity of disease in mice with EAE. 61,62 In addition, Elhofy and colleagues 63 have reported that overproduction of the chemokine CCL2 in vivo downregulates Th1 immune responses, resulting in mice with an attenuated form of EAE. Thus, our finding that double-Tg animals overproducing CXCL1 after administration of doxycycline display a milder course of MOG-EAE, compared with single-Tg and wild-type mice, is in line with the wide variety of effects that chemokines might have on CNS inflammation.…”

Increased Foxp3+ CD4+ Regulatory T Cells with Intact Suppressive Activity but Altered Cellular Localization in Murine Lupus

“…30 To elucidate the molecule(s) responsible for the altered localization of T reg cells, we next analyzed the expression of chemokine receptors involved in the function of T reg cells [31][32][33][34] by flow cytometry. Both Foxp3 ϩ and Foxp3 Ϫ CD4 ϩ T cells in the spleen showed decreased CCR7 expression ( Figure 4C) and enhanced CXCR4 expression ( Figure 4E) in aged BWF1 mice.…”

Opposing Roles for CXCR3 Signaling in Central Nervous System Versus Ocular Inflammation Mediated by the Astrocyte-Targeted Production of IL-12

“…This finding argues for a strong diseasepromoting function of the CXCR3 chemokine system in IL-12-induced neuroinflammation in the GFAP-IL12 model and is in contrast to previous findings in EAE, where CXCR3 has a disease-limiting function independent of the recruitment of effector T cells to the CNS. 24,37 The gross reduction of leukocytes in the parenchyma and subarachnoid space of GF-IL12/CXCR3KO mice provides evidence of a functional role of CXCR3 in mediating the leukocyte accumulation in the CNS as a result of IL-12 overproduction. However, CXCR3 deficiency did not completely prevent cerebellar inflammation in all GF-IL12/CXCR3KO mice.…”

“…6,36 In particular, studies of EAE did not reveal the expected diseasepromoting effect of CXCR3 but rather protective and disease-limiting functions. 24,37 We examined the role of CXCR3 in a less complex T H 1-mediated model of spontaneous CNS inflammation in transgenic mice with astrocytetargeted production of IL-12. Within the CNS of these mice with CXCR3 deficiency, we observed a markedly attenuated inflammatory response, which corresponded with the well-characterized impact of the CXCR3 chemokine system on the migration and attraction of type 1 immune cells.…”

“…In experimental autoimmune encephalomyelitis (EAE), CXCR3 surprisingly has a protective effect, which is demonstrated by a more severe and chronic disease in CXCR3-deficient mice. 24 However, EAE has a complex pathogenesis, which is not, as previously assumed, a mainly T H 1-driven autoimmune reaction. Different T-cell subsets-T H 1, T H 17, and Tregs-have an impact during different stages of the disease, and to understand these functions is currently an important issue in neuroimmunology.…”