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

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 and Elizabeth D. Mellins ()
Additional contact information
Wei Jiang: Stanford University School of medicine
James R. Birtley: University of Massachusetts Medical School
Shu-Chen Hung: 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
Birgitte Kornum: Rigshospitalet
Lu Tian: Stanford University School of Medicine
Huang Huang: Stanford University School of Medicine
Lital Adler: Stanford University School of medicine
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
Lawrence J. Stern: University of Massachusetts Medical School
Elizabeth D. Mellins: Stanford University School of medicine

Nature Communications, 2019, vol. 10, issue 1, 1-17

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-13234-x

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