B cell-intrinsic insulin resistance as a mechanism of obesity-linked immune dysfunction 3949

Abstract Description Obesity predisposes to insulin resistance, a pathophysiological state that is accompanied by a multifaceted dysregulation of the immune system. In obese individuals, aberrant nutritional, endocrine and gut microbial signals promote a state of meta-inflammation that disrupts insulin signaling and metabolic homeostasis. As demonstrated in past pandemic such as H1N1 influenza (2019), these metabolic and immune alterations culminated in detrimental impairments to both vaccine-induced and natural antiviral immunity. Despite these observations, if and how metabolic inflammation impacts protective immunity against foreign pathogens remains largely understudied. We observed that obesity altered B cell differentiation, function, and insulin receptor. Thus, we set out to test whether B cell-intrinsic insulin resistance impairs B cell-mediated immunity, using an animal model of B cell-targeted genetic deletion of the insulin receptor. We found that insulin signalling converges with BCR signaling to modulate antibody class switch recombination and affinity maturation, and that loss of insulin receptor on B cells dampened antibody responses to vaccination and H1N1 influenza infection. These findings suggest potential points of modulation in the Insulin receptor signaling pathway to boost B cell-mediated protective immunity. Funding Sources CIHR461888 Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)