In situ expansion of T cells that recognize distinct self-antigens sustains autoimmunity in the CNS

What drives the progression of CNS autoimmunity? Ramadan et al. show that in a mouse model of multiple sclerosis, disease is initiated by T cells that react to myelin, while disease progression depends on cross-reactive T cells that also recognise neuronal antigens.What drives the progression of CNS autoimmunity? Ramadan et al. show that in a mouse model of multiple sclerosis, disease is initiated by T cells that react to myelin, while disease progression depends on cross-reactive T cells that also recognise neuronal antigens.Polyspecific T cells recognizing multiple distinct self-antigens have been identified in multiple sclerosis and other organ-specific autoimmune diseases, but their pathophysiological relevance remains undetermined. Using a mouse model of multiple sclerosis, we show that autoimmune encephalomyelitis induction is strictly dependent on reactivation of pathogenic T cells by a peptide (35-55) derived from myelin oligodendrocyte glycoprotein (MOG). This disease-inducing response wanes after onset. Strikingly, the progression of disease is driven by the in situ activation and expansion of a minority of MOG(35-55)-specific T cells that also recognize neurofilament-medium (NF-M)(15-35,) an intermediate filament protein expressed in neurons. This mobilization of bispecific T cells is critical for disease progression as adoptive transfer of NF-M(15-35/)MOG(35-55) bispecific T cell lines caused full-blown disease in wild-type but not NF-M-deficient recipients. Moreover, specific tolerance through injection of NF-M15-35 peptide at the peak of disease halted experimental autoimmune encephalomyelitis progression. Our findings highlight the importance of polyspecific autoreactive T cells in the aggravation and perpetuation of central nervous system autoimmunity.