Diet-induced obesity impairs induction of Experimental Autoimmune Encephalomyelitis and is restored by PD-1 blockade

Abstract

Abstract Obesity has marked effects on immune function and is associated with increased infection susceptibility and decreased adaptive immune response. We examined the effects of obesity on adaptive autoimmune responses using a diet-induced obesity mouse model. The pathogenesis of experimental autoimmune encephalomyelitis (EAE), a model of autoimmune demyelinating disease of CNS, is mediated by autoreactive Th1 and Th17 CD4 T cell subsets. 8–9-month-old C57Bl/6 male mice were fed 60% fat or 10% fat control diet starting at 6–8 weeks old and were immunized with 300 μg of rodent myelin oligodendrocyte glycoprotein (MOG)35–55 peptide in complete Freund’s adjuvant (CFA) containing 5 mg/ml heat-killed M. tuberculosis. Control diet mice exhibited onset of severe clinical symptoms of hind limb paralysis similarly to young wild-type controls, while diet-induced obese mice experienced a significantly delayed onset. Clinical scores correlated with greater number of MOG-specific tetramer-positive CD4 T cells and number of IFN-gamma and IL-17a-expressing CD4 T cells in the CNS of control mice compared to obese mice. Decreased functional cytokine expression and proliferation called into question the exhaustive nature of T cells in obese mice through the upregulation of the PD-1/PD-L1 pathway, a known regulator of EAE. We treated EAE-induced mice on control and high-fat diet with anti-PD-1 blockade (29F.1A12) and restored EAE induction in both clinical score and number of pathologic CD4 T cells in the CNS of obese mice. Our findings may indicate an impairment of the adaptive immune system through the PD-1/PD-L1 pathway in obesity, possibly indicating an augmentation of the checkpoint pathway in settings of systemic inflammation.