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In vivo clonal expansion and phenotypes of hypocretin-specific CD4+ T cells in narcolepsy patients and controls

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  • Wei Jiang
  • James R Birtley
  • Shu-Chen Hung
  • Weiqi Wang
  • Shin-Heng Chiou
  • Claudia Macaubas
  • Birgitte Kornum
  • Lu Tian
  • Huang Huang
  • Lital Adler
  • Grant Weaver
  • Liying Lu
  • Alexandra Ilstad-Minnihan
  • Sriram Somasundaram
  • Sashi Ayyangar
  • Mark M Davis
  • Lawrence J Stern
  • Elizabeth D Mellins
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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 α (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+ TCRαβ clonotypes encoded by identical α/β 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.

Original languageEnglish
JournalNature Communications
Volume10
Issue number1
Pages (from-to)5247
ISSN2041-1723
DOIs
Publication statusPublished - 20 Nov 2019

ID: 59153837