Background

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.

Objective

We hypothesized that CD4⁺ T-cell lymphopenia could be associated with a state of T-cell exhaustion in previously transplanted SCID patients.

Methods

We analyzed markers of exhaustion in blood samples from 61 SCID patients at a median of 10.4 years after HCT.

Results

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.

Conclusions

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.

中文翻译：

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移植后 T 细胞重建不良的严重联合免疫缺陷幸存者的异常 T 细胞耗竭

 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生存。尽管同种异体 HCT 取得了成功，但许多 SCID 患者经历了不完全的免疫重建、持续的 T 细胞淋巴细胞减少和长期预后不佳。

 客观的

我们假设 CD4 ⁺ T 细胞淋巴细胞减少症可能与先前接受移植的 SCID 患者的 T 细胞耗竭状态有关。

 方法

我们分析了 61 名 SCID 患者在 HCT 后平均 10.4 年的血液样本中的疲劳标志物。

 结果

与 HCT 后 CD4 ⁺ T 细胞计数正常的 SCID 患者相比，T 细胞重建不良的患者显示初始 CD45RA ⁺ /CCR7 ⁺ T 细胞、近期胸腺移出和 TCR 切除圈的频率较低。他们的总和初始 CD8 ⁺ T 细胞上的 TCR 库也受到限制，抑制性受体（PD-1、2B4、CD160、BTLA、CTLA-4）表达增加，激活标记物（HLA-DR、穿孔素）增加。分别表明 T 细胞耗竭和异常激活。 CD8 ⁺ T 细胞的耗竭评分与 CD4 ⁺ T 细胞计数、近期胸腺移出、TCR 切除圈和 TCR 多样性呈负相关。接受无条件 HCT 的人的疲惫评分较高，尤其是距离 HCT 较远的时候。 CD4 ⁺ T细胞较少的患者表现出疲惫的转录特征。

 结论

由于 SCID 的无条件 HCT 的接受者可能会因 T 谱系细胞产生减少而出现 HCT 后晚期 T 细胞衰竭。 T 细胞上抑制性受体表达升高可能是长期 T 细胞重建不良的生物标志物。