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

Author

Listed:
  • Wei Jiang

    (Stanford University School of medicine
    Stanford University School of Medicine)

  • James R. Birtley

    (University of Massachusetts Medical School
    UCB Pharma)

  • Shu-Chen Hung

    (Stanford University School of medicine
    Stanford University School of Medicine)

  • Weiqi Wang

    (Stanford University School of Medicine)

  • Shin-Heng Chiou

    (Stanford University School of Medicine)

  • Claudia Macaubas

    (Stanford University School of medicine
    Stanford University School of Medicine)

  • Birgitte Kornum

    (Rigshospitalet)

  • Lu Tian

    (Stanford University School of Medicine)

  • Huang Huang

    (Stanford University School of Medicine)

  • Lital Adler

    (Stanford University School of medicine
    Weizmann Institute of Science)

  • Grant Weaver

    (University of Massachusetts Medical School)

  • Liying Lu

    (University of Massachusetts Medical School)

  • Alexandra Ilstad-Minnihan

    (Stanford University School of medicine)

  • Sriram Somasundaram

    (Stanford University School of medicine)

  • Sashi Ayyangar

    (Stanford University School of medicine)

  • Mark M. Davis

    (Stanford University School of Medicine
    Stanford University School of Medicine
    Stanford University)

  • Lawrence J. Stern

    (University of Massachusetts Medical School)

  • Elizabeth D. Mellins

    (Stanford University School of medicine
    Stanford University School of Medicine)

Abstract

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.

Suggested Citation

  • 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-Min, 2019. "In vivo clonal expansion and phenotypes of hypocretin-specific CD4+ T cells in narcolepsy patients and controls," Nature Communications, Nature, vol. 10(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-13234-x
    DOI: 10.1038/s41467-019-13234-x
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    Cited by:

    1. Hanna M. Ollila & Eilon Sharon & Ling Lin & Nasa Sinnott-Armstrong & Aditya Ambati & Selina M. Yogeshwar & Ryan P. Hillary & Otto Jolanki & Juliette Faraco & Mali Einen & Guo Luo & Jing Zhang & Fang H, 2023. "Narcolepsy risk loci outline role of T cell autoimmunity and infectious triggers in narcolepsy," Nature Communications, Nature, vol. 14(1), pages 1-13, December.

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