Recognition of viral and self-antigens by T1 and T1/T17 central memory cells in patients with multiple sclerosis reveals distinct roles in immune surveillance and relapses.

BACKGROUND

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) that is caused by autoreactive T cells and associated with viral infections. However, the phenotype of pathogenic T cells in peripheral blood remains to be defined, and how viruses promote MS is debated.

OBJECTIVE

We aimed to identify and characterize potentially pathogenic autoreactive T cells, as well as protective antiviral T cells, in patients with MS.

METHODS

We analyzed CD4 helper T-cell subsets from peripheral blood or cerebrospinal fluid for cytokine production, gene expression, plasticity, homing potentials, and their reactivity to self-antigens and viral antigens in healthy subjects and patients with MS. Moreover, we monitored their frequencies in untreated and fingolimod- or natalizumab-treated patients with MS.

RESULTS

T1/T17 central memory (T1/T17) cells were selectively increased in peripheral blood of patients with relapsing-remitting MS with a high disease score. T1/T17 cells were closely related to conventional T17 cells but had more pathogenic features. In particular, they could shuttle between lymph nodes and the CNS and produced encephalitogenic cytokines. The cerebrospinal fluid of patients with active MS was enriched for CXCL10 and contained mainly CXCR3-expressing T1 and T1/T17 subsets. However, while T1 cells responded consistently to viruses, T1/T17 cells reacted strongly with John Cunningham virus in healthy subjects but responded instead to myelin-derived self-antigens in patients with MS. Fingolimod and natalizumab therapies efficiently targeted autoreactive T1/T17 cells but also blocked virus-specific T1 cells.

CONCLUSIONS

We propose that autoreactive T1/T17 cells expand in patients with MS and promote relapses after bystander recruitment to the CNS, whereas T1 cells perform immune surveillance. Thus the selective targeting of T1/T17 cells could inhibit relapses without causing John Cunningham virus-dependent progressive multifocal encephalomyelitis.