Cytotoxic CD4+CD28 null T lymphocytes, systemic inflammation and atherosclerotic risk in patients with chronic kidney disease.
OBJECTIVE
The CD4(+) T cell subset lacking surface CD28 plays a role in atherosclerotic cardiovascular disease. The association between CD4(+)CD28(null) T cells and early atherosclerotic changes in chronic kidney disease (CKD) has never been investigated. We evaluated the frequency of circulating CD4(+)CD28(null) 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(+)CD28(null) 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(+)CD28(null) cells was found to be significantly higher compared to CD4(+)CD28(+) cells (p < 0.0001). A larger proportion of CD4(+)CD28(null) 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(+)CD28(null) 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(+)CD28(null) 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(+)CD28(null) T lymphocyte population. CD4(+)CD28(null) 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.
Department of Nephrology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
Ashok Kumar
AK
Yadav
Anupam
A
Lal
Vivekanand
V
Jha
D000368:Aged; D050197:Atherosclerosis / Q000097:blood / Q000209:etiology* / Q000276:immunology*; D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000276:immunology; D018106:CD28 Antigens / Q000032:analysis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002340:Carotid Artery Diseases / Q000097:blood / Q000209:etiology* / Q000276:immunology*; D059168:Carotid Intima-Media Thickness; D016022:Case-Control Studies; D003430:Cross-Sectional Studies; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D005919:Glomerular Filtration Rate; D053804:Granzymes / Q000276:immunology; D006801:Humans; D015850:Interleukin-6 / Q000276:immunology; D007676:Kidney Failure, Chronic / Q000097:blood / Q000150:complications* / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D054353:Perforin / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
D015415:Biomarkers; D018106:CD28 Antigens; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D054353:Perforin; D002097:C-Reactive Protein; D053804:Granzymes