背景:严重联合免疫缺陷(SCID)包括罕见的遗传性免疫疾病,需要通过造血细胞移植(HCT)或基因治疗进行明确治疗才能存活。尽管同种异体HCT取得了成功,许多SCID患者经历不完全的免疫重建,持续性T细胞淋巴细胞减少症,和糟糕的长期结果。
目的:我们假设在之前移植的SCID患者中,CD4+T细胞淋巴细胞减少可能与T细胞耗尽状态有关。
方法:我们分析了61例SCID患者在HCT后中位数为10.4年的血液样本中的疲惫标志物。
结果:与CD4+T细胞计数正常的HCT后SCID患者相比,那些T细胞重建不良的患者显示幼稚CD45RA+/CCR7+T细胞的频率较低,最近的胸腺移民,和TCR切除圈。他们的TCR曲目也有限制,抑制性受体的表达增加(PD-1,2B4,CD160,BTLA,CTLA-4),和增加的激活标记(HLA-DR,穿孔素)对它们的总和幼稚CD8+T细胞,提示T细胞耗尽和异常激活,分别。CD8+T细胞耗竭评分与CD4+T细胞计数呈负相关,最近的胸腺移民,TCR切除圆,和TCR多样性。非条件HCT接受者的排气评分较高,特别是在离HCT更远的时候。具有较少CD4+T细胞的患者显示出耗尽的转录特征。
结论:SCID的非条件HCT的接受者可能由于T谱系细胞产生减少而导致HCT后晚期T细胞衰竭。抑制性受体在其T细胞上的表达升高可能是不良长期T细胞重建的生物标志物。
Severe combined immunodeficiency (SCID) comprises rare inherited disorders of immunity that require definitive treatment through hematopoietic cell transplantation (HCT) or gene therapy for survival. Despite successes of allogeneic HCT, many SCID patients experience incomplete immune reconstitution, persistent T-cell lymphopenia, and poor long-term outcomes.
We hypothesized that CD4+ T-cell lymphopenia could be associated with a state of T-cell exhaustion in previously transplanted SCID patients.
We analyzed markers of exhaustion in blood samples from 61 SCID patients at a median of 10.4 years after HCT.
Compared to post-HCT SCID patients with normal CD4+ T-cell counts, those with poor T-cell reconstitution showed lower frequency of naive CD45RA+/CCR7+ T cells, recent thymic emigrants, and TCR excision circles. They also had a restricted TCR repertoire, increased expression of inhibitory receptors (PD-1, 2B4, CD160, BTLA, CTLA-4), and increased activation markers (HLA-DR, perforin) on their total and naive CD8+ T cells, suggesting T-cell exhaustion and aberrant activation, respectively. The exhaustion score of CD8+ T cells was inversely correlated with CD4+ T-cell count, recent thymic emigrants, TCR excision circles, and TCR diversity. Exhaustion scores were higher among recipients of unconditioned HCT, especially when further in time from HCT. Patients with fewer CD4+ T cells showed a transcriptional signature of exhaustion.
Recipients of unconditioned HCT for SCID may develop late post-HCT T-cell exhaustion as a result of diminished production of T-lineage cells. Elevated expression of inhibitory receptors on their T cells may be a biomarker of poor long-term T-cell reconstitution.