The Insulin Receptor Plays a Critical Role in T Cell Function and Adaptive Immunity

Abstract

T cell activation is an energy-demanding process fueled by increased glucose consumption and accompanied by upregulation of the insulin receptor (INSR). In this article, we report that silencing the INSR in inducible knockdown rats impairs selective T cell functions but not thymocyte development. Glucose transport and glycolysis in activated CD4 T cells were compromised in the absence of the INSR, which was associated with alterations in intracellular signaling pathways. The observed metabolic defects coincided with reduced cytokine production, proliferation, and migration, as well as increased apoptosis of CD4 T cells. The cytotoxicity of CD8 T cells in response to alloantigens was also diminished under these conditions, whereas the frequency and suppressive capacity of regulatory T cells were unaffected. The observed impairments proved to be decisive in vivo because silencing of the INSR attenuated clinical symptoms in animal models of acute graft-versus-host disease and multiple sclerosis. Taken together, our results suggest that upregulation of the INSR on T cells following activation is required for efficient adaptive immunity.

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.…”

“…We previously reported that insulin reduced IL-10 production from mouse T regs in an Akt-mTOR-dependent manner, resulting in impaired suppression of inflammatory cytokine production by myeloid cells (Han et al, 2014). Investigation into the role of the insulin receptor (Insr) in conventional CD4 + T cells (T convs) revealed that insulin signaling promoted their inflammatory function in vivo (Fischer et al, 2017;Tsai et al, 2018). How insulin signaling affected T regs in vivo in the context of normal or elevated levels of insulin, however, remained unknown.…”

Nutrient-sensing kinase signaling in bovine immune cells is altered during the postpartum nutrient deficit: A possible role in transition cow inflammatory response

“…The upregulation of the INSR protein expression could be due to a more activated immune cell state as certain immune cell subsets increase the expression of the receptor in response to stimulation and to direct glucose toward the cells (Maratou et al, 2007;Fischer et al, 2017). Alternatively, it is possible that the linear increase in protein expression is part of the physiological adaptation to the nutrient deficit postpartum and upregulation may serve as a glucose scavenging mechanism during the time of the nadir in circulating insulin concentrations typically observed in the postpartum period (Mann et al, 2016a).…”

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

“…Indeed, insulin has been previously shown to promote in vitro T cell proliferation when supplied exogenously. More recently, use of a whole-body knockdown of the Insr in rats linked insulin signaling to T cell function, although this model was confounded by underlying hyperglycemia associated with systemic loss of INSR action (Fischer et al, 2017). The mechanistic links between INSR and T cell function in vivo using cell-type-specific knockdown mouse models, and in mouse models of infectious diseases, remain uncharacterized.…”