IL-7 induces sCD127 release and mCD127 downregulation in human CD8+ T cells by distinct yet overlapping mechanisms, both of which are impaired in HIV infection.,European Journal of Immunology

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IL-7 induces sCD127 release and mCD127 downregulation in human CD8+ T cells by distinct yet overlapping mechanisms, both of which are impaired in HIV infection.
European Journal of Immunology ( IF 4.5 ) Pub Date : 2020-05-11 , DOI: 10.1002/eji.201948453
Sandra C Côté ₁ , Stephanie C Burke Schinkel ₁ , Tamara K Berthoud _{1,

2} , Priscila O Barros _{1,

2} , Maria Sanchez-Vidales _{1,

2} , April M Davidson _{1,

2} , Angela M Crawley _{1,

2,

3} , Jonathan B Angel _{1,

2,

4}

Affiliation

The IL‐7 receptor specific α chain, CD127, can be expressed both as a membrane‐associated (mCD127) and a soluble form (sCD127), however, the mechanisms involved in their regulation remain to be defined. We first demonstrated in primary human CD8⁺ T cells that IL‐7‐induced downregulation of mCD127 expression is dependent on JAK and PI3K signaling, whereas IL‐7‐induced sCD127 release is also mediated by STAT5. Following stimulation with IL‐7, expression of alternatively spliced variants of the CD127 gene, sCD127 mRNA, is reduced, but to a lesser degree than the full‐length gene. Evaluation of the role of proteases revealed that MMP‐9 was involved in sCD127 release, without affecting the expression of mCD127, suggesting it does not induce direct shedding from the cell surface. Since defects in the IL‐7/CD127 pathway occur in various diseases, including HIV, we evaluated CD8⁺ T cells derived from HAART‐treated HIV‐infected individuals and found that IL‐7‐induced (1) downregulation of mCD127, (2) release of sCD127, and (3) expression of the sCD127 mRNA were all impaired. Expression of mCD127 and sCD127 is, therefore, regulated by distinct, but overlapping, mechanisms and their impairment in HIV infection contributes to our understanding of the CD8⁺ T cell dysfunction that persists despite effective antiretroviral therapy.

中文翻译：

IL-7通过独特但重叠的机制诱导人CD8 + T细胞中sCD127的释放和mCD127的下调，两者在HIV感染中均受损。

IL-7受体特异性α链CD127既可以表达为膜相关（mCD127），也可以表达为可溶性形式（sCD127），但是，其调控机制尚待确定。我们首先在人类原始CD8 ^{+中进行了}演示IL-7诱导的mCD127表达下调的T细胞取决于JAK和PI3K信号传导，而IL-7诱导的sCD127释放也由STAT5介导。用IL-7刺激后，CD127基因的可变剪接变体sCD127 mRNA的表达减少，但程度小于全长基因。对蛋白酶作用的评估表明，MMP-9参与了sCD127的释放，而没有影响mCD127的表达，表明它不会诱导直接从细胞表面脱落。由于IL-7 / CD127途径的缺陷发生在包括HIV在内的多种疾病中，因此我们评估了CD8 ⁺来自经HAART治疗的HIV感染者的T细胞，发现IL-7诱导的（1）mCD127的下调，（2）sCD127的释放和（3）sCD127 mRNA的表达均受损。因此，mCD127和sCD127的表达受不同但重叠的机制调控，它们在HIV感染中的损伤有助于我们理解CD8 ⁺ T细胞功能障碍，尽管有效的抗逆转录病毒疗法仍然存在。

更新日期：2020-05-11

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