In vivo clonal expansion and phenotypes of hypocretin-specific CD4+ T cells in narcolepsy patients and controls
Open Access
- 20 November 2019
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Communications
- Vol. 10 (1), 5247
- https://doi.org/10.1038/s41467-019-13234-x
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.Keywords
Funding Information
- GlaoSmithKline Biologicals SA
- The Child Health Research Institute, Lucile Packard Foundation for Children’s Health, as well as the Stanford CTSA
This publication has 57 references indexed in Scilit:
- T cells in patients with narcolepsy target self-antigens of hypocretin neuronsNature, 2018
- Isolation of a Structural Mechanism for Uncoupling T Cell Receptor Signaling from Peptide-MHC BindingCell, 2018
- Absence of anti-hypocretin receptor 2 autoantibodies in post pandemrix narcolepsy casesPLOS ONE, 2017
- CD4+ T-Cell Reactivity to Orexin/Hypocretin in Patients With Narcolepsy Type 1Sleep, 2016
- Antibodies to influenza nucleoprotein cross-react with human hypocretin receptor 2Science Translational Medicine, 2015
- Structural Basis of Specificity and Cross-Reactivity in T Cell Receptors Specific for Cytochrome c–I-EkPublished by The American Association of Immunologists ,2011
- Common variants in P2RY11 are associated with narcolepsyNature Genetics, 2010
- Joint X-ray and neutron refinement withphenix.refineActa Crystallographica Section D-Biological Crystallography, 2010
- Functionally Impaired HIV-Specific CD8 T Cells Show High Affinity TCR-Ligand InteractionsThe Journal of Immunology, 2004
- A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brainsNature Medicine, 2000