Figure 3.

Key Figure: Viral Reactivation Could Lead to Bystander Recruitment of Autoreactive Central Memory T Helper Type 1/17 (Th1/17_CM) Cells

(A) In healthy individuals, the central nervous system (CNS) is surveyed by antiviral T cells. Upon viral reactivation (i), IP-10 is induced via IFNs and leads to the recruitment of antiviral CXCR3⁺ T cells, likely both Th1/17- and Th1 cells, to the CNS parenchyma from the blood stream (ii). Antiviral T cells rapidly control the virus, and tissue repair mechanisms ensure that damage to the CNS is limited. Relapses could be triggered when the same immune surveillance mechanism leads to the erroneous bystander recruitment of autoreactive Th1/17_CM cells to the CNS in patients with multiple sclerosis (MS). In addition, infected CXCR3⁺ B cells could be recruited that transport viruses, such as Epstein-Barr virus (EBV) and John Cunningham virus (JCV) to the CNS. Th1/17_CM cells in patients with MS, but not in healthy individuals, react with myelin-derived self-antigens and, thus, could attack healthy, uninfected tissues, inducing extensive tissue damage and relapses (iii). (B) Alternatively, autoreactive Th1/17_CM cells could home spontaneously to the CNS parenchyma via CCR6 during the remission phase of patients with MS (i), and induce de novo viral reactivations and, consequently, the recruitment of CXCR3⁺ lymphocytes (ii). Reactivation of viruses in the CNS induced by autoreactive Th1/17_CM cells could either trigger relapses or represent an amplification loop of virus-induced relapses. Notably, autoreactive Th17 cells in healthy individuals could also induce viral reactivation in the CNS by this mechanism, but they are less pathogenic.