Dysfunction of CD8\u2009+\u2009PD-1\u2009+\u2009T cells in type 2 diabetes caused by the impairment of metabolism-immune axis

Ichiro Nojima,Satoshi Miyamoto,Yoshiko Hada,Heiichiro Udono,Nahoko Tomonobu,Shingo Eikawa,Nobuo Kajitani,Haruhito A Uchida,Kenichi Shikata,Sanae Teshigawara,Atsuko Nakatsuka,Jun Eguchi,Atsuhito Tone,Jun Wada

doi:10.1038/s41598-020-71946-3

Abstract

The metabolic changes and dysfunction in CD8 + T cells may be involved in tumor progression and susceptibility to virus infection in type 2 diabetes (T2D). In C57BL/6JJcl mice fed with high fat-high sucrose chow (HFS), multifunctionality of CD8 + splenic and tumor-infiltrating lymphocytes (TILs) was impaired and associated with enhanced tumor growth, which were inhibited by metformin. In CD8 + splenic T cells from the HFS mice, glycolysis/basal respiration ratio was significantly reduced and reversed by metformin. In the patients with T2D (DM), multifunctionality of circulating CD8 + PD-1 + T cells stimulated with PMA/ionomycin as well as with HLA-A*24:02 CMV peptide was dampened, while metformin recovered multifunctionality. Both glycolysis and basal respiration were reduced in DM, and glycolysis was increased by metformin. The disturbance of the link between metabolism and immune function in CD8 + PD-1 + T cells in T2D was proved by recovery of antigen-specific and non-specific cytokine production via metformin-mediated increase in glycolytic activity.

Highlights

The metabolic changes and dysfunction in CD8 + T cells may be involved in tumor progression and susceptibility to virus infection in type 2 diabetes (T2D)
In this glucose tolerance test, blood glucose levels and area under the curve (AUC) were elevated in HFS compared with standard chow diet (STD), while glucose tolerance was improved in HFS + Met (Fig. 1B)
We demonstrated that circulating CD8 + PD-1 + population derived from the patients with T2D was reduced

Summary

Introduction

The metabolic changes and dysfunction in CD8 + T cells may be involved in tumor progression and susceptibility to virus infection in type 2 diabetes (T2D). In the patients with T2D (DM), multifunctionality of circulating CD8 + PD-1 + T cells stimulated with PMA/ionomycin as well as with HLA-A*24:02 CMV peptide was dampened, while metformin recovered multifunctionality Both glycolysis and basal respiration were reduced in DM, and glycolysis was increased by metformin. The cancer cells have been long known to undergo alterations in glucose and amino acid metabolism to respond to bioenergic needs for rapid proliferation, i.e. metabolic reprogramming. Vigorous glucose consumption by tumor cells metabolically compete with infiltrating T cells and hyponutrition in T cells reduced mammalian target of rapamycin (mTOR) activity, glycolysis and cytokine production such as interferon (IFN)-γ. We investigated peripheral CD8 + T cells derived from the patients with T2D and their alterations by the treatment with metformin by evaluating the cytokine production and metabolic states by flux analyzer

Methods

Results

Conclusion