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

• Published in: Nature communications Vol. 10; no. 1; p. 5247
• Main Authors: Jiang, Wei, Birtley, James R, Hung, Shu-Chen, Wang, Weiqi, Chiou, Shin-Heng, Macaubas, Claudia, Kornum, Birgitte, Tian, Lu, Huang, Huang, Adler, Lital, Weaver, Grant, Lu, Liying, Ilstad-Minnihan, Alexandra, Somasundaram, Sriram, Ayyangar, Sashi, Davis, Mark M, Stern, Lawrence J, Mellins, Elizabeth D
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 20.11.2019; Nature Publishing Group UK; Nature Portfolio
• Subjects: Alleles; Animals; Antigens; Autoimmunity - genetics; Autoimmunity - immunology; Case-Control Studies; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; Cell Proliferation; Crystallography, X-Ray; Drosophila; Effector cells; Epitopes; Expansion; Histocompatibility antigen HLA; HLA-DQ Antigens - genetics; HLA-DQ Antigens - immunology; Humans; Immunoglobulin Joining Region - genetics; In vivo methods and tests; Leukocytes; Lymphocytes; Lymphocytes T; Narcolepsy; Narcolepsy - genetics; Narcolepsy - immunology; Orexins; Orexins - immunology; Peripheral Tolerance; Phenotype; Phenotypes; Receptors, Antigen, T-Cell, alpha-beta - genetics; Receptors, Antigen, T-Cell, alpha-beta - immunology; Science & Technology - Other Topics; Sleep; Sleep disorders; T cell receptors
• ISSN: 2041-1723; 2041-1723
• 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 HCRT . 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.