Targeting interferon-{lambda} signaling promotes recovery from central nervous system autoimmunity

Abstract

Type III interferons (IFNLs) are newly discovered cytokines, acting at epithelial and other barriers, that exert immunomodulatory functions in addition to their primary roles in antiviral defense. Here we define a role for IFNLs in maintaining autoreactive T cell effector function and limiting recovery in a murine model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE). Genetic or antibody-based neutralization of the IFNL receptor (IFNLR) resulted in lack of disease maintenance during EAE, with loss of CNS Th1 effector responses and limited axonal injury. Phenotypic effects of IFNLR signaling were traced to increased antigen presenting cell (APC) function, with associated increase in T cell production of IFN{gamma} and GM-CSF. Consistent with this, IFNL levels within lesions of CNS tissues derived from MS patients were elevated compared to MS normal appearing white matter (NAWM). Furthermore, expression of IFNLR was selectively elevated in MS active lesions compared to inactive lesions or NAWM. These findings suggest IFNL signaling as a potential therapeutic target to prevent chronic autoimmune neuroinflammation.