Effects of conventional immunosuppressive treatment on CD244+ (CD28null) and FOXP3+ T cells in the inflamed muscle of patients with polymyositis and dermatomyositis.
Effects of conventional immunosuppressive treatment on CD244+ (CD28null) and FOXP3+ T cells in the inflamed muscle of patients with polymyositis and dermatomyositis.
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DOI：
10.1186/s13075-016-0974-5
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发表时间：
2016-04-01
影响因子：
4.9
通讯作者：
Malmström V
中科院分区：
文献类型：
--
作者：
Pandya JM;Loell I;Hossain MS;Zong M;Alexanderson H;Raghavan S;Lundberg IE;Malmström V
尽管进行了积极的免疫抑制治疗，多发性肌炎 (PM) 和皮肌炎 (DM) 患者的肌肉组织中仍可能存在 T 细胞浸润。在这里，我们研究了受影响肌肉中持久性 T 细胞在多大程度上是 FOXP3+（调节性 T 细胞 (Treg) 的标记物）或 CD244+（CD28null T 细胞的标记物），以及它们的存在是否与临床结果相关。还研究了 CD28null T 细胞对糖皮质激素和 Treg 介导的免疫抑制的敏感性。采用免疫组织化学方法研究了 16 名新诊断或未经治疗的 PM/DM 患者的肌肉活检，以检测糖皮质激素和免疫抑制剂治疗前后 CD3、FOXP3 和 CD244 的表达。为了进行临床评估，测量了肌酸激酶的血清水平、肌肉性能（FI 和 MMT8）、疾病活动度（MITAX）和残疾（HAQ）。通过 CD69 上调来测量糖皮质激素和 Tregs 对 T 细胞活化的体外抑制作用。治疗前，发炎肌肉中 CD244+ 细胞的比例高于 FOXP3+ 细胞。治疗后，FOXP3+ 细胞数量减少，而 CD244+ 细胞数量持续存在。与 FI > 75% 的患者相比，治疗后肌肉功能受损 (<75% FI) 的患者在后续活检中 CD244+ 细胞水平更高。 MITAX 和 HAQ 与治疗后 CD244+ 细胞的数量相关。与 CD28+ T 细胞相比，CD4+CD28null T 细胞在体外对糖皮质激素和 Treg 介导的免疫抑制表现出较低的敏感性。免疫抑制治疗后肌炎患者的不良预后与肌肉组织中 CD244+（CD28null）T 细胞的持续存在有关，这表明它们对免疫抑制具有抵抗力。鉴于调节性 T 细胞最近在肌肉组织再生中的作用，调节性 T 细胞的相对丧失也可能导致临床结果不佳。
T-cell infiltrates may persist in muscle tissue of polymyositis (PM) and dermatomyositis (DM) patients despite aggressive immunosuppressive treatment. Here, we investigated to what extent persistent T cells in affected muscle were FOXP3+, a marker for regulatory T cells (Tregs), or CD244+, a marker for CD28null T cells, and whether their presence correlated to clinical outcome. The sensitivity of CD28null T cells towards glucocorticoid and Treg-mediated immunosuppression was also investigated. Muscle biopsies from 16 newly diagnosed or untreated patients with PM/DM were investigated by immunohistochemistry for expression of CD3, FOXP3 and CD244 before and after treatment with glucocorticoids and immunosuppressive agents. For clinical evaluation, serum levels of creatine kinase, muscle performance (FI and MMT8), disease activity (MITAX) and disability (HAQ) were measured. In vitro suppressive effects of glucocorticoids and Tregs on T-cell activation were measured by CD69 upregulation. Before treatment, CD244+ cells were present at higher proportions compared to FOXP3+ cells in the inflamed muscle. Following treatment, FOXP3+ cell numbers decreased while CD244+ cells persisted. Patients with impaired muscle function (<75 % FI) post-treatment had higher levels of CD244+ cells in the follow-up biopsy compared to those with FI >75 %. MITAX and HAQ correlated with the number of CD244+ cells post-treatment. CD4+CD28null T cells displayed lower sensitivity towards both glucocorticoid and Treg-mediated immunosuppression in vitro compared to their CD28+ counterparts. Poor outcome in patients with myositis following immunosuppressive therapy was linked to persistence of CD244+ (CD28null) T cells in muscle tissue, suggesting their resistance against immunosuppression. A relative loss of regulatory T cells could also contribute to poor clinical outcome given their recently ascribed role in muscle tissue regeneration.