Cytotoxic CD4+CD28null T lymphocytes, systemic inflammation and atherosclerotic risk in patients with chronic kidney disease

摘要

Background/Aims: The CD4+ T cell subset lacking surface CD28 plays a role in atherosclerotic cardiovascular disease. The association between CD4+CD28null T cells and early atherosclerotic changes in chronic kidney disease (CKD) has never been investigated. We evaluated the frequency of circulating CD4+CD28null cells in 128 CKD and 62 control subjects. Methods: Phenotype (CD4 and CD28) and cytotoxic potential (perforin and granzyme B expression) were studied by flow cytometry. Systemic inflammation (hsCRP, IL-6 and TNF-α) was analyzed by ELISA. Common carotid artery intima-media thickness (CCA-IMT) was measured with an ultrasound system. The effect of TNF-α and IL-6 on these cells was evaluated in vitro. Results: The frequency of CD4+CD28null cells was significantly increased in CKD patients (10.14 ± 0.8 vs. 3.53 ± 0.36, p 0.0001). The expression of perforin and granzyme B on CD4 +CD28null cells was found to be significantly higher compared to CD4+CD28+ cells (p 0.0001). A larger proportion of CD4+CD28null cells obtained from CKD subjects showed the expression of perforin and granzyme B compared to those from healthy controls. CKD patients showed increased CCA-IMT (p 0.0001). CD4+CD28null cells were positively correlated with the IMT (r = 0.505, p 0.0001). CKD subjects showed increased levels of hsCRP, IL-6 and TNF-α. Only the TNF-α level showed a correlation with CD4 +CD28null cells (r = 0.45, p 0.0001). In vitro treatment with TNF-α but not IL-6 resulted in further downregulation of CD28 on the CD4+ T cell surface. Conclusions: CKD subjects exhibit an increase in the circulating cytotoxic CD4+CD28null T lymphocyte population. CD4+CD28null cell expansion correlated with preclinical atherosclerotic changes. TNF-α shows a specific relationship and might have a role in the expansion of this subset in CKD.