Natural killer cell function, an important target for infection and tumor protection, is impaired in type 2 diabetes.

Jeannig Berrou,Marion Venot,Sophie Fougeray,Antoine Toubert,Marie-Noëlle Peraldi,Nicolas Dulphy,Jean-François Gautier,Victor Chardiny,Golo Ahlenstiel

doi:10.1371/journal.pone.0062418

Abstract

Patients with Type 2 diabetes (T2D) are highly susceptible to infection and have an increased incidence of some tumors, possibly due to immune system dysfunction. In the innate cellular immune system, Natural Killer (NK) lymphocytes are important effectors responsible for controlling infections and combating tumor development. We analyzed NK cell subsets in 51 patients with long-standing T2D. Compared with healthy blood donors, diabetic patients showed a profound decrease in both NKG2D-positive NK cells (44% vs. 55.5%, P<0.01) and NKp46-positive cells (26% vs. 50%, P<0.01). Decreased expression of these receptors was associated with functional defects, such as reduced NK degranulation capacity when challenged with the tumor target cell line K562 (10.3 vs. 15.8%, P<0.05). This defect could be restored in vitro by stimulating NK cells from T2D patients with IL-15 (P<0.05). NKG2D expression was found to be negatively correlated with HBA1c level (r = −0.50; P = 0.009), suggesting that sustained hyperglycemia could directly influence NK cell defects. We demonstrated that endoplasmic reticulum (ER) stress, an important mediator in diabetes-associated complications, was inducible in vitro in normal NK cells and that tunicamycin treatment resulted in a significant decrease in NKG2D expression (P<0.05). Furthermore, markers of the Unfolded Protein Response (UPR) BiP, PDI and sXBP1 mRNAs were significantly increased in NK cells from T2D patients (P<0.05, P<0.01, P<0.05, respectively), indicating that ER stress is activated in vivo through both PERK and IRE1 sensors. These results demonstate for the first time defects in NK cell-activating receptors NKG2D and NKp46 in T2D patients, and implicate the UPR pathway as a potential mechanism. These defects may contribute to susceptibility to infections and malignancies and could be targetted therapeutically.

Highlights

Clinicians are well aware that patients with type 2 diabetes (T2D) are highly susceptible to infections and are prone to malignancy [1,2]
Because we suspected a role for natural killer (NK) cells in the T2D phenotype, we focused on specific NK cell receptors (Table 2): NKG2D, NKG2C, NKp30, NKp44, NKp46 - all of which are activating receptors, and NKG2A and Killer cell Immunoglobulin-like Receptors (KIRs) which include inhibitory receptors [13]
NK cells play a crucial role in controlling infections and tumors, but little data is available on this cell subset in T2D patients

Summary

Introduction

Clinicians are well aware that patients with type 2 diabetes (T2D) are highly susceptible to infections and are prone to malignancy [1,2]. This predisposition has been known for decades, the underlying mechanisms causing this immune dysfunction remain unclear. Polymorphonuclear leukocytes have been shown to produce increased levels of reactive oxygen species, possibly as a result of the effects of hyperglycemia [6]. Oxidative stress was recently shown to modulate natural killer (NK) cell functions in a cohort of patients with end-stage renal failure who show increased production of reactive oxygen species [7]. The NK population is of particular interest in the context of T2D as NK cells are known to play an important role in defending the body against infections and tumors [10,11]

Objectives

Methods

Results

Conclusion