Sharma Vishal, Pope Brandon J, Santiago Nathan V, Boland Molly T, Sun Dongmei, Reynolds Richard J, Szalai Alexander J, Bridges S Louis, Raman Chander
The University of Alabama at Birmingham.
ACR Open Rheumatol. 2021 Apr;3(4):277-283. doi: 10.1002/acr2.11244. Epub 2021 Mar 28.
We investigated whether a previously reported association of IFNGR expression with rheumatoid arthritis (RA) and its radiographic severity reflects differences in proximal interferon-γ (IFN-γ) signaling in T cells from patients with RA compared with healthy controls (HC).
Using phosphoflow cytometry, we compared IFN-γ-stimulated signal transducer and activator of transcription 1 (STAT1) activation in CD4 and CD8 T-cell populations from patients with RA and HC.
Compared with controls, patients with RA had a higher proportion of CD4 T cells, associated with expansion of the CD4 effector memory subset. Several CD4 T-cell types exhibited reduced IFN-γ-induced phosphoSTAT1 (pSTAT1 ) in patients with RA compared with HC. Engaging the T-cell receptor (TCR) complex on CD4 T cells during IFN-γ stimulation abrogated the reduction in STAT1 activation in patients with RA but had no effect in HC. The phosphorylation of STAT1 was similar in CD4 T cells from patients with RA and HC. In contrast to CD4 T cells, IFN-γ-induced pSTAT1 levels in CD8 T cells were equivalent or higher in patients with RA compared with HC. Total STAT1 levels (phosphorylated + unphosphorylated) were lower in CD4 and CD8 T cells from patients with RA compared with HC.
We report diminished IFN-γ-induced pSTAT1 levels in CD4 T cells in patients with RA, which were restored by TCR engagement. There were lower levels of total STAT1 in patients with RA compared with HC, but this likely does not explain diminished IFN-γ-induced pSTAT1 levels in CD4 T cells because activation in CD8 T cells was higher or equivalent to that seen in HC. The enhanced IFNGR expression in patients with RA reported previously may reflect a compensatory mechanism to overcome deficiency in IFN-γ responsiveness.
我们研究了先前报道的干扰素γ受体（IFNGR）表达与类风湿关节炎（RA）及其放射学严重程度之间的关联，是否反映了与健康对照（HC）相比，RA患者T细胞中近端干扰素γ（IFN-γ）信号传导的差异。
使用磷酸化流式细胞术，我们比较了RA患者和HC的CD4和CD8 T细胞群体中IFN-γ刺激的信号转导和转录激活因子1（STAT1）的激活情况。
与对照组相比，RA患者的CD4 T细胞比例更高，这与CD4效应记忆亚群的扩增有关。与HC相比，几种CD4 T细胞类型在RA患者中表现出IFN-γ诱导的磷酸化STAT1（pSTAT1）减少。在IFN-γ刺激期间激活CD4 T细胞上的T细胞受体（TCR）复合物可消除RA患者中STAT1激活的减少，但对HC无效。RA患者和HC的CD4 T细胞中STAT1的磷酸化情况相似。与CD4 T细胞相反，与HC相比，RA患者CD8 T细胞中IFN-γ诱导的pSTAT1水平相当或更高。与HC相比，RA患者的CD4和CD8 T细胞中总STAT1水平（磷酸化+未磷酸化）较低。
我们报告了RA患者CD4 T细胞中IFN-γ诱导的pSTAT1水平降低，通过TCR激活可恢复。与HC相比，RA患者的总STAT1水平较低，但这可能无法解释CD4 T细胞中IFN-γ诱导的pSTAT1水平降低，因为CD8 T细胞中的激活高于或等同于HC中的激活。先前报道的RA患者中IFNGR表达增强可能反映了一种补偿机制，以克服IFN-γ反应性的缺陷。
