The primary objective of the proposed studies is to test a novel hypothetical model of optical neuritis with the overall goal of pinpointing druggable therapeutic targets. Optic neuritis is a condition involving primary inflammation of the optic nerve. Acutely it is associated with loss of vision or double vision and is often the first presentation of multiple sclerosis. Several lines of evidence indicate that it is a multifactorial, autoimmune condition involving T-cell mediated demyelination of the optic nerve, but it has proven difficult to distinguish causative responses from bystander effects. To provide a framework for identification of causative responses in the context of multifactorial interactions, we have developed mouse models of optic neuritis that combine constitutive overexpression of interleukin-2 (IL-2) with HSV-1 infection through ocular infection with recombinant HSV-IL-2 virus or delivery of IL-2 into the brains of mice using Alzet osmotic mini-pumps prior to ocular infection with wild-type HSV-1. Both CD4+ and CD8+ T cells contribute to the HSV-1/IL-2-induced optic nerve and CNS pathology and the pathology resembles that of the MOG35?55 EAE model. The current models are distinct, however, in that they demonstrate that, in the context of viral infection, IL-2 can drive optic nerve and CNS demyelination. Preliminary analysis of the interactions required for the IL-2-driven pathology using knockout, depletion, adoptive transfer and/or blocking approaches have provided novel insights pinpointing a potential requirement for interactions between IL-2 and the IL-2r? (but not IL-2r? or IL-2r?) subunit as well as the association of a single amino acid mutation of IL-2 with blockade of pathogenesis; a potential requirement for type 2 innate lymphoid (ILC2) cells, with ILC1 or ILC3 playing no role; and a potential requirement for production of IL-17A by the ILC2 cells. Engagement of either the IL-17RA or IL-17RC receptor on TH17 cells appears to drive CNS demyelination. Macrophages and IL-12p70 appear to play protective roles in this model. Collectively, these data suggest a hypothetical model in which elevation of IL-2 in the context of viral infection drives an autoaggressive TH17 response that causes optic neuritis and CNS pathology through generation of IL-17-producing ILC2s. We will test this hypothesis by defining the cytokine/receptor interactions and responses of ILC subtypes in these models to: (1) Determine whether the presence of ILC2 is required for optic nerve/CNS pathology; (2) Determine whether ILC2-production of IL-17A contributes to optic nerve/CNS pathology by promoting a TH17 response; and (3) Determine the interplay between ILC2 cell responses and macrophage production of IL-12p70 in demyelination. CLINICAL RELEVANCE: Optic neuritis is a prototypic inflammatory autoimmune disease that is closely associated with MS. Confirmation of the proposed hypothetical model will have broad implications in terms of advancing the understanding of the interactions of environmental signals and host susceptibility factors that generate autoimmune responses and will provide a conceptual framework for the design of more effective therapeutic targeting for resolution and/or blocking of optic neuritis in some patients with this condition.