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Hypocretin-specific CD4+ T cells in narcolepsy patients and controls: in vivo clonal expansion and phenotypes

ABSTRACT: Individuals with narcolepsy suffer from abnormal sleep patterns due to loss of neurons that uniquely supply hypocretin (HCRT). Previous studies found the associations of narcolepsy with 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. However, DQ6+ individuals generate DQ6-HCRT tetramer+/TRAJ24+ TCRs. Without a proof that an HCRT-reactive cell expressing such TCRs has expanded in vivo, T cell-mediated autoimmunity in narcolepsy remains speculative. Here, we isolated DQ6-HCRT tetramer+/CD4+ T cells (low frequency, <0.04%) from DQ6+ individuals with/without narcolepsy. Within 74 informative TRAJ24+ TCRαβ from 8/12 patients and 11/12 controls, we identified a conserved family of clonotypes shared by 2 patients and 2 controls using identical α/β genes. TRAJ24-G allele+ clonotypes only expanded in the two patients, whereas a TRAJ24-C allele+ clonotype expanded in a control. A representative tetramer+/G-allele+ TCR showed signaling reactivity to the physiologically modified form of the epitope HCRT87-97. Clonally expanded G-allele+ T cells also exhibited an unconventional effector phenotype. In vivo expansion of HCRT-reactive TRAJ24-G allele+ cells provides critical evidence for an autoimmune contribution to narcolepsy development.

ORGANISM(S): Homo sapiens

PROVIDER: GSE135852 | GEO | 2019/10/15

REPOSITORIES: GEO

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