CXC chemokine receptor 4 expressed in T cells plays an important role in the development of collagen-induced arthritis

Abstract

Introduction

Chemokines and their receptors are potential therapeutic targets in rheumatoid arthritis (RA). Among these, several studies suggested the involvement of CXC chemokine 4 (CXCR4) and its ligand CXC ligand 12 (SDF-1) in RA pathogenesis. However, the role of these molecules in T-cell function is not known completely because of embryonic lethality of Cxcr4- and Cxcl12-deficient mice. In this report, we generated T cell-specific Cxcr4-deficient mice and showed that the CXCR4 in T cells is important for the development of collagen-induced arthritis (CIA).

Methods

T cell-specific Cxcr4-deficient mice were generated by using the Cre-loxP system. Mice harboring loxP sites flanking exon 2 of the Cxcr4gene ( Cxcr4 ^flox/flox ) were generated by homologous recombination and crossed with Cre transgenic mice expressing Cre recombinase under the control of Lck promoter ( Cxcr4 ^+/+ / Lck-Cremice) to generate T cell-specific Cxcr4-deficient mice ( Cxcr4 ^flox/flox / Lck-Cre mice). CIA was induced by immunization with chicken type II collagen and Complete Freund's Adjuvant (CFA).

Results

The incidence, but not the severity, of CIA was significantly reduced in Cxcr4 ^flox/flox / Lck-Cre mice compared with Cxcr4 ^+/+/Lck-Cre mice. We found that the expression of CXCR4 was enhanced in activated T cells, and the migration of Cxcr4-deficient T cells toward SDF-1 was severely impaired. However, antibody production, cellular proliferative response, and cytokine production on treatment with type II collagen (IIC) were normal in these knockout mice, suggesting that CXCR4 is not involved in T-helper functions. Interestingly, the proportion of CXCR4-expressing T cells was much increased in affected joints compared with that in draining lymph nodes in CIA-induced mice, and distribution of Cxcr4 ^flox/flox / Lck-Cre mouse-derived T cells into affected joints was suppressed compared with that in Cxcr4 ^+/+/Lck-Cre T cells.

Conclusions

These results indicate that CXCR4 expression in T cells is important for the development of CIA, by recruiting activated T cells toward inflammatory sites, and suggest that CXCR4 is a good target for the treatment of RA in humans.