Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229-3900, USA.
Immunobiology. 2011 Sep;216(9):971-8. doi: 10.1016/j.imbio.2011.03.012. Epub 2011 Apr 7.
Dendritic cells (DCs) have long been recognized as potential therapeutic targets of rheumatoid arthritis (RA). Increasing evidence has showed that DCs are capable of suppressing autoimmunity by expanding FoxP3⁺ regulatory T cells (T(reg)), which in turn exert immunosuppression by increasing TGFβ-1. In the SKG mice, activated DC prime autoreactive T cells causing autoantibody production and an inflammatory arthritic response. Recently, we reported that CC-chemokine receptor-2 deficient (Ccr2⁻/⁻) mice had impaired DCs migration and reduced CD8α⁺ DCs in the C57Bl/6J mice strain and that these mice were more susceptible to collagen antibody-induced arthritis (CAIA), compared to wild type mice. To examine the mechanism by which DCs contribute to the increased susceptibility of arthritis in Ccr2⁻/⁻ mice, we tested the hypothesis that CD8α⁺ DCs are protective (tolerogenic) against autoimmune arthritis by examining the role of CD8α⁺ DCs in Ccr2⁻/⁻ and SKG mice.
To examine the mechanism by which DCs defects lead to the development of arthritis, we used two murine models of experimental arthritis: collagen-induced arthritis (CIA) in DBA1/J mice and zymosan-induced arthritis in SKG mice. DBA1/J mice received recombinant fms-like tyrosine kinase 3 ligand (Flt3L) injections to expand endogenous DCs populations or adoptive transfers of CD8α⁺ DCs.
Flt3L-mediated expansion of endogenous CD8α⁺ DCs resulted in heightened susceptibility of CIA. In contrast, supplementation with exogenous CD8α⁺ DCs ameliorated arthritis in Ccr2⁻/⁻ mice and enhanced TGFβ1 production by T cells. Furthermore, SKG mice with genetic inactivation of CCR2 did not affect the numbers of DCs nor improve the arthritis phenotype.
CD8α⁺ DCs were tolerogenic to the development of arthritis. CD8α⁺ DCs deficiency heightened the sensitivity to arthritis in Ccr2⁻/⁻ mice. Ccr2 deficiency did not alter the arthritic phenotype in SKG mice suggesting the arthritis in Ccr2⁻/⁻ mice was T cell-independent.
树突状细胞（DC）一直被认为是类风湿关节炎（RA）的潜在治疗靶点。越来越多的证据表明，DC 能够通过扩增 FoxP3⁺调节性 T 细胞（Treg）来抑制自身免疫，而 Treg 则通过增加 TGFβ-1 发挥免疫抑制作用。在 SKG 小鼠中，激活的 DC 可激活自身反应性 T 细胞，导致自身抗体产生和炎症性关节炎反应。最近，我们报道 CCR2 缺陷（Ccr2⁻/⁻）小鼠在 C57Bl/6J 小鼠品系中出现 DC 迁移受损和 CD8α⁺DC 减少，与野生型小鼠相比，这些小鼠更容易发生胶原抗体诱导的关节炎（CAIA）。为了研究 DC 对 Ccr2⁻/⁻小鼠关节炎易感性增加的作用机制，我们通过研究 CD8α⁺DC 在 Ccr2⁻/⁻和 SKG 小鼠中的作用，检验了 CD8α⁺DC 对自身免疫性关节炎具有保护（耐受原性）作用的假设。
为了研究 DC 缺陷导致关节炎发展的机制，我们使用了两种实验性关节炎的小鼠模型：DBA1/J 小鼠的胶原诱导关节炎（CIA）和 SKG 小鼠的酵母聚糖诱导关节炎。DBA1/J 小鼠接受重组 fms 样酪氨酸激酶 3 配体（Flt3L）注射以扩增内源性 DC 群体或过继转移 CD8α⁺DC。
Flt3L 介导的内源性 CD8α⁺DC 扩增导致 CIA 易感性增加。相比之下，外源性 CD8α⁺DC 的补充改善了 Ccr2⁻/⁻小鼠的关节炎，并增强了 T 细胞产生的 TGFβ1。此外，CCR2 基因缺失的 SKG 小鼠对 DC 数量没有影响，也没有改善关节炎表型。
CD8α⁺DC 对关节炎的发生具有耐受原性。CD8α⁺DC 缺乏会增加 Ccr2⁻/⁻小鼠对关节炎的敏感性。CCR2 缺失并未改变 SKG 小鼠的关节炎表型，表明 Ccr2⁻/⁻小鼠的关节炎是 T 细胞非依赖性的。
