In vivo clonal expansion and phenotypes of hypocretin-specific CD4+ T cells in narcolepsy patients and controls
In vivo clonal expansion and phenotypes of hypocretin-specific CD4+ T cells in narcolepsy patients and controls
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DOI：
10.1038/s41467-019-13234-x
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发表时间：
2019-11-20
影响因子：
16.6
通讯作者：
Mellins, Elizabeth D.
中科院分区：
文献类型：
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作者：
Jiang, Wei;Birtley, James R.;Mellins, Elizabeth D.
发作性睡病患者的睡眠模式异常是由于失去了唯一供应下丘脑泌素(HCRT)的神经元。以前的研究发现发作性睡病与人类白细胞抗原(HLA)-DQ6等位基因和T细胞受体α(TRA)J24基因片段有关，也表明体外刺激的T细胞可以靶向HCRT。在这里，我们提出了DQ6-HCRT四聚体+/TRAJ24(+)/CD4(+)T细胞在DQ6(+)伴和不伴发作性睡病患者体内扩增的证据。我们从两名患者和两名对照中鉴定出由相同的α/β基因区域编码的相关TRAJ24(+)TCRα/β克隆型。TRAJ24-G等位基因+克隆型仅在两个患者中扩大，而TRAJ24-C等位基因(+)克隆型在对照组中扩大。一个具有代表性的四聚体(+)/G等位基因(+)TCR对表位HCRT87-97显示出信号反应性。克隆性扩增的G等位基因(+)T细胞表现出非传统的效应表型。我们对HCRT反应的TRAJ24(+)细胞体内扩增的分析为进一步研究自身免疫在发作性睡病发展中的作用开辟了一条途径。
Individuals with narcolepsy suffer from abnormal sleep patterns due to loss of neurons that uniquely supply hypocretin (HCRT). Previous studies found associations of narcolepsy with the human leukocyte antigen (HLA)-DQ6 allele and T-cell receptor alpha (TRA) J24 gene segment and also suggested that in vitro-stimulated T cells can target HCRT. Here, we present evidence of in vivo expansion of DQ6-HCRT tetramer+/TRAJ24(+)/CD4(+) T cells in DQ6(+) individuals with and without narcolepsy. We identify related TRAJ24(+) TCR alpha beta clonotypes encoded by identical alpha/beta gene regions from two patients and two controls. TRAJ24-G allele+ clonotypes only expand in the two patients, whereas a TRAJ24-C allele(+) clonotype expands in a control. A representative tetramer(+)/G-allele(+) TCR shows signaling reactivity to the epitope HCRT87-97. Clonally expanded G-allele(+) T cells exhibit an unconventional effector phenotype. Our analysis of in vivo expansion of HCRT-reactive TRAJ24(+) cells opens an avenue for further investigation of the autoimmune contribution to narcolepsy development.