Abstract
Despite obesity reaching pandemic proportions, its impact on antigen-specific T cell responses is still unclear. We have recently demonstrated that obesity results in increased expression of PD-1 on T cells, and checkpoint blockade targeting PD-1/PD-L1 surprisingly resulted in greater clinical efficacy in cancer therapy. Adverse events associated with this therapy center around autoimmune reactions. In this study, we examined the impact of obesity on T cell priming and on autoimmune pathogenesis using the mouse model experimental autoimmune encephalomyelitis (EAE), which is mediated by autoreactive myelin-specific T cells generated after immunization. We observed that diet-induced obese (DIO) mice had a markedly delayed EAE onset and developed milder clinical symptoms compared to mice on control diet (CD). This delay was associated with impaired generation of myelin-specific T cell numbers and concurrently correlated with increased PD-L1 upregulation on antigen-presenting cells in secondary lymphoid organs. PD-1 blockade during the priming stage of EAE restored disease onset and severity and increased numbers of pathogenic CD4+ T cells in the central nervous system (CNS) of DIO mice to similar levels to those of CD mice. Administration of anti–PD-1 after onset of clinical symptoms did not increase EAE pathogenesis demonstrating that initial priming is the critical juncture affected by obesity. These findings demonstrate that obesity impairs antigen-specific T cell priming, but this can be reversed with PD-1 blockade. Our results further suggest that PD-1 blockade may increase the risk of autoimmune toxicities, particularly in obesity.
Highlights
According to the CDC National Center for Health Statistics, approximately 40% of adults in the United States are overweight (defined as body mass index (BMI) 25 ≤ x < 30) or obese (BMI ≥ 30 kg/m2)
This resulted in decreased infiltration of the central nervous system (CNS) by peripheral immune cells and milder EAE clinical course in diet-induced obese (DIO) mice compared to control diet (CD) mice
The impairment of T cell responses after immunization was correlated with enhanced upregulation of PD-L1 expression on APCs in DIO mice compared to CD mice
Summary
According to the CDC National Center for Health Statistics, approximately 40% of adults in the United States are overweight (defined as body mass index (BMI) 25 ≤ x < 30) or obese (BMI ≥ 30 kg/m2). Diet-induced obesity has been found to both promote and inhibit immune responses [1, 2]. Increasing accumulation and activation of immune cells in adipose tissue promotes chronic low-grade inflammation [1], and obesity has been linked with autoimmune diseases, including inflammatory bowel disease (IBD), ankylosing spondylitis, multiple sclerosis (MS), and psoriasis [3, 4]. Heightened inflammatory responses in obesity may in part be attributed to potentiation of proinflammatory macrophages at steady state [5, 6]. Obesity is associated with increased immunosuppression, impaired innate immune cell function, and immune exhaustion, resulting in ineffective immune responses in infections and cancer [7,8,9,10,11]. Poorer vaccine responses have been correlated with increasing BMI [12, 13]
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