NF-κB2 Controls the Migratory Activity of Memory T Cells by Regulating Expression of CXCR4 in a Mouse Model of Sjögren’s Syndrome

Objective. Dysregulated chemokine signaling contributes to autoimmune diseases by facilitating aberrant T-cell infiltration into target tissues, but the specific cytokines, receptors, and T-cell populations remain largely unidentified. Role of the potent chemokine CXCL12 and its receptor CXCR4 in T-cell autoimmune response was examined using alymphoplasia (aly)/aly mice, a Sjögren’s syndrome (SS) model.
Methods. T-cell phenotypes in the salivary gland of aly/aly mice were evaluated using immunological analysis. In vitro migration assay was used to assess T-cell migratory activity toward several chemokines. Gene expression of chemokine receptors, and transforming growth factor (TGF)β receptors was measured with quantitative reverse transcription-polymerase chain reaction. The CXCR4 antagonist AMD3100 was administered to the aly/aly mice 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 aly/+ TEM cells. CXCL12 expression was specifically upregulated in the SS target cells of aly/aly mice. TEM cells from RelB−/− mice, but not nuclear factor (NF)-κB1−/− mice, also showed high migratory activity toward CXCL12, implicating a nonclassical NF-κB2/RelB pathway in the regulation of TEM cell migration. TEM cells from aly/aly mice also overexpressed TGFβ receptors I and II. The CXCR4 antagonist AMD3100 suppressed autoimmune lesions in aly/aly mice by reducing TEM cell infiltration.
Conclusion. Our results suggest that the NF-κB2/RelB 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 treating autoimmune diseases.

内容要旨・審査要旨・論文本文の公開
本論文は，著者Mie Kurosawaの学位論文として提出され，学位審査・授与の対象となっている。

This is the peer reviewed version of the following article: Kurosawa, M. , Arakaki, R. , Yamada, A. , Tsunematsu, T. , Kudo, Y. , Sprent, J. and Ishimaru, N. (2017), NF‐κB2 Controls the Migratory Activity of Memory T Cells by Regulating Expression of CXCR4 in a Mouse Model of Sjögren's Syndrome. Arthritis Rheumatol, 69: 2193-2202, which has been published in final form at https://doi.org/10.1002/art.40230. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.