Pro-inflammatory cytokines of a T helper-1-signature are known to promote insulin resistance (IR) in obesity, but the physiological role of this mechanism is unclear. It is also unknown whether and how viral infection induces loss of glycemic control in subjects at risk for developing diabetes mellitus type 2 (DM2). We have found in mice and humans that viral infection caused short-term systemic IR. Virally-induced interferon-γ (IFN-γ) directly targeted skeletal muscle to downregulate the insulin receptor but did not cause loss of glycemic control because of a compensatory increase of insulin production. Hyperinsulinemia enhanced antiviral immunity through direct stimulation of CD8 effector T cell function. In pre-diabetic mice with hepatic IR caused by diet-induced obesity, infection resulted in loss of glycemic control. Thus, upon pathogen encounter, the immune system transiently reduces insulin sensitivity of skeletal muscle to induce hyperinsulinemia and promote antiviral immunity, which derails to glucose intolerance in pre-diabetic obese subjects. VIDEO ABSTRACT.

Hobit-expressing effector CD8 + T cells are T RM precursors, whose formation is regulated by the T-box transcription factor Eomes.

The activation of natural killer (NK) cells depends on a change in the balance of signals from inhibitory and activating receptors. The activation threshold values of NK cells are thought to be set by engagement of inhibitory receptors during development. Here, we found that the activating receptor NKG2D specifically set the activation threshold for the activating receptor NCR1 through a process that required the adaptor DAP12. As a result, NKGD2-deficient (Klrk1) mice controlled tumors and cytomegalovirus infection better than wild-type controls through the NCR1-induced production of the cytokine IFN-γ. Expression of NKG2D before the immature NK cell stage increased expression of the adaptor CD3ζ. Reduced expression of CD3ζ in Klrk1 mice was associated with enhanced signal transduction through NCR1, and CD3ζ deficiency resulted in hyper-responsiveness to stimulation via NCR1. Thus, an activating receptor developmentally set the activity of another activating receptor on NK cells and determined NK cell reactivity to cellular threats.

The memory CD8 T-cell pool must select for clones that bind immunodominant epitopes with high affinity to efficiently counter reinfection. At the same time, it must retain a level of clonal diversity to allow recognition of pathogens with mutated epitopes. How the level of diversity within the memory pool is controlled is unclear, especially in the context of a selective drive for antigen affinity. We find that preservation of clones that bind the activating antigen with low affinity depends on expression of the transcription factor Eomes in the first days after antigen encounter. Eomes is induced at low activating signal strength and directly drives transcription of the prosurvival protein Bcl-2. At higher signal intensity, T-bet is induced which suppresses Bcl-2 and causes a relative survival advantage for cells of low affinity. Clones activated with high-affinity antigen form memory largely independent of Eomes and have a proliferative advantage over clones that bind the same antigen with low affinity. This causes high-affinity clones to prevail in the memory pool, despite their relative survival deficit. Genetic or therapeutic targeting of the Eomes/Bcl-2 axis reduces the clonal diversity of the memory pool, which diminishes its ability to respond to pathogens carrying mutations in immunodominant epitopes. Thus, we demonstrate on a molecular level how sufficient diversity of the memory pool is established in an environment of affinity-based selection.

Diabetes mellitus type 2 (T2D) causes an increased risk of morbidity and mortality in response to viral infection. T2D is characterized by hyperglycemia and is typically associated with insulin resistance and compensatory hyperinsulinemia. CD8 T cells express the insulin receptor and previously we have shown that insulin is able to directly modulate effector CD8 T cell function. We therefore hypothesized memory CD8 T cell responsiveness in context of T2D is negatively impacted by hyperinsulinemia or hyperglycemia. Using a mouse model for T2D we could show that memory CD8 T cell function was significantly reduced in response to re-challenge by viral infection or with melanoma cells. Basal insulin injection of mice increased GLUT-1 expression and glucose uptake in memory CD8 T cell precursors early after infection, which was prevented when these cells were deficient for the insulin receptor. However, neither insulin injection, nor insulin receptor deficiency resulted in a difference in metabolism, memory formation, cytokine production or recall responses of memory CD8 T cells compared to controls. Importantly, in context of obesity, insulin receptor deficiency on CD8 T cells did not affect the functional capacity of memory CD8 T cells. In contrast, we could show in vitro and in vivo that hyperglycemia significantly impairs the antiviral capacity of memory CD8 T cells. Our findings indicate that obesity impairs the memory CD8 T cell response against viral infection and cancer through the detrimental effects of hyperglycemia rather than hyperinsulinemia.