Reduced immunomodulation potential of bone marrow-derived mesenchymal stem cells induced CCR4 ⁺CCR6 ⁺ Th/Treg cell subset imbalance in ankylosing spondylitis

Abstract

Introduction

Ankylosing spondylitis (AS) is a chronic autoimmune disease, and the precise pathogenesis is largely unknown at present. Bone marrow-derived mesenchymal stem cells (BMSCs) with immunosuppressive and anti-inflammatory potential and Th17/Treg cells with a reciprocal relationship regulated by BMSCs have been reported to be involved in some autoimmune disorders. Here we studied the biological and immunological characteristics of BMSCs, the frequency and phenotype of CCR4 ⁺CCR6 ⁺ Th/Treg cells and their interaction in vitro in AS.

Methods

The biological and immunomodulation characteristics of BMSCs were examined by induced multiple-differentiation and two-way mixed peripheral blood mononuclear cell (PBMC) reactions or after stimulation with phytohemagglutinin, respectively. The interactions of BMSCs and PBMCs were detected with a direct-contact co-culturing system. CCR4 ⁺CCR6 ⁺ Th/Treg cells and surface markers of BMSCs were assayed using flow cytometry.

Results

The AS-BMSCs at active stage showed normal proliferation, cell viability, surface markers and multiple differentiation characteristics, but significantly reduced immunomodulation potential (decreased 68 ± 14%); the frequencies of Treg and Fox-P3 ⁺ cells in AS-PBMCs decreased, while CCR4 ⁺CCR6 ⁺ Th cells increased, compared with healthy donors. Moreover, the AS-BMSCs induced imbalance in the ratio of CCR4 ⁺CCR6 ⁺ Th/Treg cells by reducing Treg/PBMCs and increasing CCR4 ⁺CCR6 ⁺ Th/PBMCs, and also reduced Fox-P3 ⁺ cells when co-cultured with PBMCs. Correlation analysis showed that the immunomodulation potential of BMSCs has significant negative correlations with the ratio of CCR4 ⁺CCR6 ⁺ Th to Treg cells in peripheral blood.

Conclusions

The immunomodulation potential of BMSCs is reduced and the ratio of CCR4 ⁺CCR6 ⁺ Th/Treg cells is imbalanced in AS. The BMSCs with reduced immunomodulation potential may play a novel role in AS pathogenesis by inducing CCR4 ⁺CCR6 ⁺ Th/Treg cell imbalance.