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Hyperglycemia and Not Hyperinsulinemia Mediates Diabetes-Induced Memory Cd8 T Cell Dysfunction

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posted on 19.01.2022, 16:41 authored by Inga Kavazović, Mia Krapić, Ammarina Beumer-Chuwonpad, Bojan Polić, Tamara Turk Wensveen, Niels A. Lemmermann, Klaas P.J.M. van Gisbergen, Felix M. Wensveen
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.

Funding

Deutsche Forschungsgemeinschaft 1292 European Commission > European Regional Development Fund KK.01.1.1.01.0006 Hrvatska Zaklada za Znanost IP-2016-06-8027 IP-2016-06-9306 IP-2020-02-7928 IP-CORONA-2020-04-2045 IPCH-2020-10-8440 University of Rijeka 19-41-1551

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