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

Nat Commun. 2019 Nov 20;10(1):5247. doi: 10.1038/s41467-019-13234-x.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoimmunity / genetics
  • Autoimmunity / immunology*
  • CD4-Positive T-Lymphocytes / immunology*
  • Case-Control Studies
  • Cell Proliferation
  • Crystallography, X-Ray
  • Drosophila
  • HLA-DQ Antigens / genetics
  • HLA-DQ Antigens / immunology
  • Humans
  • Immunoglobulin Joining Region / genetics
  • Narcolepsy / genetics
  • Narcolepsy / immunology*
  • Orexins / immunology*
  • Peripheral Tolerance
  • Phenotype
  • Receptors, Antigen, T-Cell, alpha-beta / genetics
  • Receptors, Antigen, T-Cell, alpha-beta / immunology


  • HCRT protein, human
  • HLA-DQ Antigens
  • HLA-DQ6 antigen
  • Immunoglobulin Joining Region
  • Orexins
  • Receptors, Antigen, T-Cell, alpha-beta