Recent evidence suggests that narcolepsy, a disorder that results from the loss of orexinergic neurons of the lateral hypothalamus, has an autoimmune aetiology, but the underlying mechanisms have not been elucidated. Here, haemagglutinin (which acted as an artificial 'self-antigen') was selectively expressed in mouse hypothalamic orexin-positive neurons, and haemagglutinin-specific T cells were then transferred into these mice. Hypothalamic infiltration by cytotoxic CD8 T cells (CTLs) (but not T helper 1 cells) was associated with destruction of orexinergic neurons and development of a narcolepsy-like phenotype, suggesting a role for CTLs in narcolepsy.