OBJECTIVE: Dysregulated chemokine signaling contributes to autoimmune diseases by facilitating aberrant T cell infiltration into target tissues, but the specific chemokines, receptors, and T cell populations remain largely unidentified. The aim of this study was to examine the role of the potent chemokine CXCL12 and its receptor CXCR4 in the T cell autoimmune response, using alymphoplasia (aly)/aly mice, a model of Sjogren's syndrome (SS). METHODS: T cell phenotypes in the salivary gland of aly/aly mice were evaluated using immunologic analysis. An in vitro migration assay was used to assess T cell migratory activity toward several chemokines. Gene expression of chemokine receptors and transforming growth factor beta receptors (TGFbetaRs) was measured by quantitative reverse transcription-polymerase chain reaction. The CXCR4 antagonist AMD3100 was administered to the aly/aly mice in order to evaluate its suppressive effect on autoimmune lesions. RESULTS: Effector memory T (TEM) cells derived from aly/aly mice demonstrated higher in vitro migratory activity toward CXCL12 than did TEM cells from aly/+ mice. CXCL12 expression was specifically up-regulated in the SS target cells of aly/aly mice. TEM cells from RelB(-/-) mice, but not Nfkb1(-/-) mice, also showed high migratory activity toward CXCL12, implicating a role of the nonclassical RelB/NF-kappaB2 pathway in the regulation of TEM cell migration. TEM cells from aly/aly mice also overexpressed TGFbetaR type I (TGFbetaRI) and TGFbetaRII. The CXCR4 antagonist AMD3100 suppressed autoimmune lesions in aly/aly mice by reducing TEM cell infiltration. CONCLUSION: Our results suggest that the RelB/NF-kappaB2 pathway regulates T cell migration to autoimmune targets through TGFbeta/TGFbetaR-dependent regulation of CXCL12/CXCR4 signaling. This suggests that these signaling pathways are potential therapeutic targets for the treatment of autoimmune diseases.
|ISBN||2326-5205 (Electronic) 2326-5191 (Linking)|
|Authors||Kurosawa, M.; Arakaki, R.; Yamada, A.; Tsunematsu, T.; Kudo, Y.; Sprent, J.; Ishimaru, N.|
|Responsible Garvan Author|
|Publisher Name||Arthritis & Rheumatology|
|URL link to publisher's version||https://www.ncbi.nlm.nih.gov/pubmed/28804991|