To study the role of the programmed death-1 (PD-1)/programmed death-1 ligand 1 (PD-L1) coinhibitory pathway in regulating CD4+CD28− T cells, and to explore the association of soluble PD-L1 (sPD-L1) in the development of T2DM with atherosclerotic macrovascular diseases.
The percentage of CD4+CD28− T lymphocyte subsets from peripheral blood mononuclear cells (PBMCs) and the expression of PD-1/PD-L1 on lymphocytes were analyzed by immunostaining and flow cytometry, respectively. The serum levels of sPD-L1 and IFN-γ were determined by ELISA system. T cell proliferation was determined by cocultivation and WST-8 incorporation.
In 125 T2DM patients and 48 healthy donors, CD4+CD28− T cells from patients with T2DM expressed higher PD-1 than that of the cells from healthy individuals, and the proliferation response of CD4+CD28− T cells could be enhanced by advanced glycation end products (AGEs). The levels of sPD-L1 in patients were also much higher than those of healthy donors, and the increase was displayed in an exacerbation-dependent manner in the T2DM with atherosclerotic macrovascular patients especially with acute coronary syndrome (ACS). The production of sPD-L1 was significantly positively correlated with the level of IFN-γ and could enhance T cell proliferation.
Both the upregulation of PD-1 and the increase of sPD-L1 were closely associated with the severity of diabetic atherosclerotic macrovascular diseases. sPD-L1 may contribute to the continuous T cell activation and development of diabetic macrovascular diseases.
Abbreviations:T2DM (Type 2 Diabetes), CVD (cardiovascular disease), PD-1 (Programmed death-1), PD-L1 (Programmed death-1 ligand 1), AGEs (advanced glycation end products), ACS (acute coronary syndrome), DC (dendritic cells), AS (atherosclerotic macrovascular complications), IMT (intima-media thickness), ELISA (Enzyme-linked immunosorbent assay), UA (unstable angina), HC (healthy controls)
To read this article in full you will need to make a payment
Purchase one-time access:Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
One-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:Subscribe to Metabolism - Clinical and Experimental
Already a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
- Advanced glycosylation end products might promote atherosclerosis through inducing the immune maturation of dendritic cells.Arterioscler Thromb Vasc Biol. 2005; 25: 2157-2163
- Advanced glycation end products: sparking the development of diabetic vascular injury.Circulation. 2006; 114: 597-605
- The multifaceted contributions of leukocyte subsets to atherosclerosis: lessons from mouse models.Nat Rev Immunol. 2008; 10: 802-815
- Normalization of obesity-associated insulin resistance through immunotherapy.Nat Med. 2009; 15: 921-929
- Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion.Nat Med. 2002; 8: 793-800
- Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade.Proc Natl Acad Sci USA. 2002; 99: 12293-12297
- Unexpected acceleration of type 1 diabetes by transgenic expression of B7-H1 in NOD mouse peri-islet glia.Diabetes. 2010; 59: 2588-2596
- PD-1/PD-L1, PD-1/PD-L2, and other co-inhibitory signaling pathways in transplantation.Transpl Int. 2008; 21: 1015-1028
- PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression.Nature. 2006; 443: 350-354
- B7-H1. A third member of the B7 family costimulates T cell proliferation and interleukin-10 secretion.Nat Med. 1999; 5: 1365-1369
- B7-DC, a new dendritic cell molecule with potent costimulatory properties for T cells.J Exp Med. 2001; 193: 839-846
- PD-L2 is a second ligand for PD-1 and inhibits T cell activation.Nat Immunol. 2001; 2: 261-268
- Laser capture microdissection-based expression profiling identifies PD1 ligand as a target of the nude locus gene product.Eur J Immunol. 2001; 31: 2497-2503
- Increased soluble and platelet-associated CD40 ligand in essential thrombocythemia and reactive thrombocytosis.Blood. 2002; 99: 2612-2614
- Serum concentrations of soluble 4-1BB and 4-1BB ligand correlated with the disease severity in rheumatoid arthritis.Exp Mol Med. 2004; 36: 13-22
- Development of a sandwich ELISA assay for evaluating soluble OX40L (CD252) in human sera of different ages or with Graves' disease.Cytokine. 2006; 36: 23-28
- Associations between soluble CD40 ligand, atherosclerosis risk factors, and subclinical atherosclerosis: results from the Dallas Heart Study.Arterioscler Thromb Vasc Biol. 2005; 25: 2192-2196
- Soluble CD40L and cardiovascular risk in women.Circulation. 2001; 104: 2266-2268
- Development of a sandwich ELISA for evaluating soluble PD-L1 (CD274) in human sera of different ages as well as supernatants of PD-L1+ cell lines.Cytokine. 2011; 56: 231-238
- CD4+CD7−CD28− T cells are expanded in rheumatoid arthritis and are characterized by autoreactivity.J Clin Invest. 1996; 97: 2027-2037
- CD4+CD28− costimulation- independent T cells in multiple sclerosis.J Clin Invest. 2001; 108: 1185-1194
- Perturbation of the T-cell repertoire in patients with unstable angina.Circulation. 1999; 100: 2135-2139
- Monoclonal T-cell proliferation and plaque instability in acute coronary syndromes.Circulation. 2000; 101: 2883-2888
- Vascular cell apoptosis in remodeling, restenosis, and plaque rupture.Circ Res. 2000; 87: 184-188
- Unusual CD4+CD28null T lymphocytes and recurrence of acute coronary events.J Am Coll Cardiol. 2007; 50: 1459-1461
- CD4-CD8 and CD28 expression in T cells infiltrating the vitreous fluid in patients with proliferative diabetic retinopathy: a flow cytometric analysis.Arch Ophthalmol. 2004; 122: 743-749
- Interferon-gamma induces major histocompatibility class II transactivator (CIITA), which mediates collagen repression and major histocompatibility class II activation by human aortic smooth muscle cells.Circ Res. 2006; 98: 472-479
- Mechanisms of insulin resistance in humans and possible links with inflammation.Hypertension. 2005; 45: 828-833
- IL-6 beta, IFN-gamma and TNF-alpha increase vulnerability of pancreatic beta cells to autoimmune destruction. J.Autoimmunity. 2003; 20: 303-312
Published online: February 11, 2013
Accepted: December 9, 2012
Received: April 7, 2012
© 2013 Elsevier Inc. Published by Elsevier Inc. All rights reserved.