NF‐κB2 Controls the Migratory Activity of Memory T Cells by Regulating Expression of CXCR4 in a Mouse Model of Sjögren's Syndrome. Issue 11 (17th October 2017)

• Record Type: Journal Article
• Authors: Kurosawa, Mie; Arakaki, Rieko; Yamada, Akiko; Tsunematsu, Takaaki; Kudo, Yasusei; Sprent, Jonathan; Ishimaru, Naozumi
• Is Part Of: Arthritis & rheumatology. Volume 69:Issue 11(2017)
• Page Start: 2193
• Page End: 2202
• Publication Date: 2017-10-17
• Subjects: Arthritis -- Periodicals; Rheumatism -- Periodicals; 616.72
• DOI: 10.1002/art.40230
• Languages: English
• ISSNs: 2326-5191

Abstract

Abstract : 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 Sjögren'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 β receptors (TGFβRs) 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‐κB2 pathway in the regulation of TEM cell migration. TEM cells from aly/aly mice also overexpressed TGFβR type I (TGFβRI) and TGFβRII. The CXCR4 antagonist AMD3100 suppressed autoimmune lesions in aly/aly mice by reducing TEM cell infiltration. Conclusion: Our results suggest that the RelB/NF‐κB2 pathway regulates T cell migration to autoimmune targets through TGFβ/TGFβR‐dependent regulation of CXCL12/CXCR4 signaling. This suggests that these signaling pathways are potential therapeutic targets for the treatment of autoimmune diseases.