Low expression and secretion of circulating soluble CTLA-4 in peripheral blood mononuclear cells and sera from type 1 diabetic children.
BACKGROUND
High levels of soluble cytotoxic T-lymphocyte antigen 4 (soluble CTLA-4), an alternative splice form of the regulatory T-cell (Treg) associated CTLA-4 gene, have been associated with type 1 diabetes (T1D) and other autoimmune diseases, such as Grave's disease and myasthenia gravis. At the same time, studies have shown soluble CTLA-4 to inhibit T-cell activation through B7 binding. This study aimed to investigate the role of soluble CTLA-4 in relation to full-length CTLA-4 and other Treg-associated markers in T1D children and in individuals with high or low risk of developing the disease.


METHODS
T1D children were studied at 4 days, 1 and 2 years after diagnosis in comparison to individuals with high or low risk of developing the disease. Isolated peripheral blood mononuclear cells were stimulated with the T1D-associated glutamic acid decarboxylase 65 and phytohaemagglutinin. Subsequently, soluble CTLA-4, full-length CTLA-4, FOXP3 and TGF-β mRNA transcription were quantified and protein concentrations of soluble CTLA-4 were measured in culture supernatant and sera.


CONCLUSIONS
Low protein concentrations of circulating soluble CTLA-4 and a positive correlation between soluble CTLA-4 mRNA and protein were seen in T1D, in parallel with a negative correlation in healthy subjects. Further, low levels of mitogen-induced soluble CTLA-4 were accompanied by low C-peptide levels. Interestingly, low mitogen-induced soluble CTLA-4 mRNA and low TGF-β mRNA expression were seen in high risk individuals, suggesting an alteration in activation and down-regulating immune mechanisms during the pre-diabetic phase.
Division of Paediatrics & Diabetes Research Centre, Department of Molecular & Clinical Medicine, Linköping University, Linköping, Sweden. anna.ryden@liu.se
Anna
A
Rydén
Caroline
C
Bolmeson
Carl-Oscar
CO
Jonson
Corrado M
CM
Cilio
Maria
M
Faresjö
D000293:Adolescent; D015551:Autoimmunity; D015415:Biomarkers; D001773:Blood Cells; D002096:C-Peptide / Q000378:metabolism; D060908:CTLA-4 Antigen / Q000096:biosynthesis / Q000097:blood* / Q000737:chemistry; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000276:immunology*; D005260:Female; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D015870:Gene Expression; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D020033:Protein Isoforms / Q000235:genetics / Q000276:immunology*; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000096:biosynthesis
D015415:Biomarkers; D002096:C-Peptide; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D020033:Protein Isoforms; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta