Abstract 15158: Altered Adaptive Immune Response in Type 2 Diabetes Mellitus: Enhanced Pro-Inflammatory Activity of CD4+CD28null T-cells in Diabetic versus non Diabetic Patients with Acute Coronary Syndromes
Background: Type 2 diabetes mellitus (DM) is associated with high risk of acute coronary syndromes (ACS); however, the mechanisms are still unknown. The unusual CD4+CD28null T-cells are expanded in ACS and predict recurrence of instability. This cells produce large amount of IFNγ, a stimulator of tissue-damaging macrophages, and express high levels of TNF-related-apoptosis-induced ligand (TRAIL) and IL12 receptor β1 (IL12R) predisposing to vascular injury. We sought to investigate the role of CD4+CD28null T-cells in DM.
Methods: CD4+CD28null T-cell functional profile and circulating mononuclear cell (MO) activation were evaluated in 20 DM patients without cardiovascular disease (cDM), 20 ACS patients with DM (ACS/DM+), 20 ACS patients without DM (ACS/DM-), and 20 controls. IFNγ production by CD4+CD28null T-cells upon stimulation with PMA and ionomycin, and the expression of TRAIL and of IL12R were assessed by 3-color flow-cytometry. IL6 and TNFα production by MO after LPS-challenge was assessed by ELISA.
Results: CD4+CD28null T-cells frequency was higher in ACS/DM+ (10.7%, 5.6–25.5) vs ACS/DM- (5.9%, 2.4–19.2), cDM (5.5%, 3.5–22.6), and controls (1.9%, 0.4–5.9) (P<0.001); also, cDM had higher CD4+CD28null T-cells than controls (P=0.001). Moreover, CD4+CD28null T-cells producing IFNγ were higher in ACS/DM+ (23.7%, 7.4–49.9) and cDM (16.9%, 6.1–56.4) than in ACS/DM- (7%, 1.4–40.8; both P<0.05) and controls (4.9%, 2-19.9; both P<0.001). CD4+CD28null T-cells expressing TRAIL and IL12R were higher in ACS/DM+ (12.2%, 5.9–98.5 and 24.6%, 11.2–70–0) vs ACS/DM- (6.5%, 1.6–55.0 and 5.5%, 0.7–49.5), cDM (4.5%, 1.7–61.3 and 7.9%, 1.1–49.4), and controls (0.7%, 0–2.5 and 2.1%, 0.5–6.7), and in cDM vs controls (all P<0.05). Finally, IL6 and TNFα production by MO was significantly higher in ACS/DM+ than in other groups (both P=0.001). In the overall population, TNFα production by MO was positively related to IFNγ producing CD4+CD28null T-cells (r=0.64 , P=0.002).
Conclusions: In DM, expanded CD4+CD28null T-cells show a more aggressive functional profile, influencing MO activation. Our results suggest a novel pathophysiologic mechanism for the increased cardiovascular risk of DM, highlighting the importance of altered adaptive immune response.
- © 2010 by American Heart Association, Inc.