Hyperglycemia and Not Hyperinsulinemia Mediates Diabetes-Induced Memory CD8 T-Cell Dysfunction

Author:

Kavazović Inga1,Krapić Mia1,Beumer-Chuwonpad Ammarina2,Polić Bojan1,Turk Wensveen Tamara34,Lemmermann Niels A.5,van Gisbergen Klaas P.J.M.2,Wensveen Felix M.1ORCID

Affiliation:

1. Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, Rijeka, Croatia

2. Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, the Netherlands

3. Center for Diabetes, Endocrinology and Cardiometabolism, Thalassotherapia, Opatija, Croatia

4. Department of Internal Medicine, Faculty of Medicine, University of Rijeka, Rijeka, Croatia

5. Institute for Virology and Research Center for Immunotherapy (FZI) at the University Medical Center of the Johannes Gutenberg University, Mainz, Germany

Abstract

Type 2 diabetes (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 that memory CD8 T-cell responsiveness in the 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 rechallenge 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 with 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.

Publisher

American Diabetes Association

Subject

Endocrinology, Diabetes and Metabolism,Internal Medicine

Reference33 articles.

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