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

Soo-Hyun Chung,Akihiko Ito,Shinobu Saijo,Keisuke Seki,Byung-Il Choi,Keiko B Kimura,Yoichiro Iwakura,Noriyuki Fujikado

doi:10.1186/ar3158

Abstract

IntroductionChemokines 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).MethodsT cell-specific Cxcr4-deficient mice were generated by using the Cre-loxP system. Mice harboring loxP sites flanking exon 2 of the Cxcr4gene (Cxcr4flox/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 (Cxcr4flox/flox/Lck-Cre mice). CIA was induced by immunization with chicken type II collagen and Complete Freund's Adjuvant (CFA).ResultsThe incidence, but not the severity, of CIA was significantly reduced in Cxcr4flox/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 Cxcr4flox/flox/Lck-Cre mouse-derived T cells into affected joints was suppressed compared with that in Cxcr4+/+/Lck-Cre T cells.ConclusionsThese 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.

Highlights

Chemokines and their receptors are potential therapeutic targets in rheumatoid arthritis (RA)
These results indicate that CXCR4 expression in T cells is important for the development of collagen-induced arthritis (CIA), by recruiting activated T cells toward inflammatory sites, and suggest that CXCR4 is a good target for the treatment of RA in humans
Tcell-specific Cxcr4-deficient mice were generated by crossing Lck-Cre transgenic mice with Cxcr4flox/flox mice To investigate the roles of CXCR4 in T cells, we generated T cell-specific conditional gene-targeted mice, as described in Materials and methods

Summary

Introduction

Chemokines and their receptors are potential therapeutic targets in rheumatoid arthritis (RA). Several studies suggested the involvement of CXC chemokine 4 (CXCR4) and its ligand CXC ligand 12 (SDF1) in RA pathogenesis. 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). The concept that humoral and cellular immunity to IIC is crucial for the development of CIA is widely accepted, multiple chemokines and cytokines are important for the pathogenesis. CXCR4 mediates migration of resting hematopoietic progenitors and B cells in response to its ligand, CXC ligand 12 (SDF-1), which is involved in various phenomena such as hematopoiesis and the development or survival of B cells [7,9]. The SDF-1-CXCR4 system is suggested to be involved in the T-cell receptor (TCR) signaling [10] or cell migration or both [6]

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