Insulin Receptor-Mediated Stimulation Boosts T Cell Immunity during Inflammation and Infection

Abstract

T cells represent a critical effector of cell-mediated immunity. Activated T cells engage in metabolic reprogramming during effector differentiation to accommodate dynamic changes in energy demands. Here, we show that the hormone, insulin, and downstream signaling through its insulin receptor shape adaptive immune function through modulating T cell metabolism. T cells lacking insulin receptor expression (LckCre+ Insr) show reduced antigen-specific proliferation and compromised production of pro-inflammatory cytokines. In vivo, T cell-specific insulin receptor deficiency reduces T cell-driven colonic inflammation. In a model of severe influenza infection with A/PR8 (H1N1), lack of insulin receptor on T cells curtails antigen-specific immunity to influenza viral antigens. Mechanistically, insulin receptor signaling reinforces a metabolic program that supports T cell nutrient uptake and associated glycolytic and respiratory capacities. These data highlight insulin receptor signaling as an important node integrating immunometabolic pathways to drive optimal T cell effector function in health and disease.

T reg–specific insulin receptor deletion prevents diet-induced and age-associated metabolic syndrome

“…Regulation of T reg function by receptor tyrosine kinase signaling is a relatively uncharted field. Insulin was previously reported to promote T conv effector function in vitro and in viral clearance (Fischer et al, 2017;Tsai et al, 2018). Our data show that insulin also directly affects T regs in the context of hyperinsulinemia.…”

‘Beauty and the beast’ in infection: How immune–endocrine interactions regulate systemic metabolism in the context of infection

“…Activated CD4 + and CD8 + T cells induce expression of the insulin receptor and its stimulation during priming promotes proliferation, cytokine production and cytotoxicity of these cells. T cell specific deletion of the insulin receptor increased lethality after influenza infection in mice, whereas it reduced pathology in a CD4 T cell dependent model of colitis . Moreover, injection of basal insulin during cytomegalovirus infection increased the anti‐viral CD8 T cell response .…”

“…As a result, both CD28 stimulation and insulin receptor triggering result in glucose transporter upregulation and induction of anabolic metabolism . Yet immune cells are not impervious to endocrine control and two recent papers using murine models have shown that insulin plays a prominent role in anti‐viral T cell responses . Activated CD4 + and CD8 + T cells induce expression of the insulin receptor and its stimulation during priming promotes proliferation, cytokine production and cytotoxicity of these cells.…”

“…Adipose tissue hormones, which communicate the status of nutrient stock availability, promote or inhibit the responsiveness of immune cells to activating stimuli in cases of nutrient abundance or shortage, respectively . Conversely, cytokines are able to influence processes normally regulated by endocrine hormones, such as hunger, body temperature and glucose uptake, as well as production of endocrine hormones themselves . Conversely, immune cells can respond directly to hormones such as insulin, which regulate systemic metabolism .…”

“…Conversely, cytokines are able to influence processes normally regulated by endocrine hormones, such as hunger, body temperature and glucose uptake, as well as production of endocrine hormones themselves . Conversely, immune cells can respond directly to hormones such as insulin, which regulate systemic metabolism . Immune–endocrine interactions in the context of metabolic disease have been well studied.…”