Reduced CCR4, interleukin-13 and GATA-3 up-regulation in response to type 2 cytokines of cord blood T lymphocytes in infants at genetic risk of type 1 diabetes.
Aberrancies in T-cell polarization including expression of chemokine receptors have been reported in human leucocyte antigen (HLA) class II associated autoimmune diseases, such as type 1 diabetes (T1D) and rheumatoid arthritis. We asked whether these aberrancies are present at birth in newborn infants carrying the HLA risk haplotypes for T1D. Sixty-seven cord blood (CB) samples from infants were screened for T1D-associated HLA risk genotypes (HLA-DR4-DQ8 and/or DR3-DQ2 without protective alleles). CB lymphocytes were stimulated with phytohaemagglutinin in type 1 (interleukin (IL)-12, anti-IL4) or type 2 (IL-4, anti-IL12) cytokine environment for 6 days. The expression of chemokine and cytokine receptors on T cells was determined by flow cytometry, secretion of cytokines was analysed with enzyme-linked immunosorbent assay, and transcription factors were analysed using real-time reverse transcriptase-polymerase chain reaction. After culture of CB lymphocytes in type 2 cytokine environment newborn infants carrying DR4-DQ8 haplotype (n=18) showed reduced percentage of CD4 T cells expressing CCR4 (P=0 x 009) and the level of CCR4 mRNA was decreased (P=0 x 008). In addition, lower secretion of IL-13 and expression of GATA-3 in CB lymphocytes cultured in type 2 cytokine environment were found in the infants with DR4-DQ8 haplotype (P=0 x 020 and P=0 x 004, respectively) in comparison to newborn infants without DR4-DQ8 and DR3-DQ2 haplotypes (n=37). Poor in vitro induction of type 2 immune responses in newborn infants with DR4-DQ8 haplotype suggests that the HLA genotype associated with risk of autoimmunity may affect the T cell polarization already at birth, which in turn may contribute to the risk for autoimmunity later in life.
Luopajärvi
Kristiina
K
Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland. kristiina.luopajarvi@hus.fi
Skarsvik
Susanne
S
Ilonen
Jorma
J
Akerblom
Hans K
HK
Vaarala
Outi
O
D016764:Cell Polarity / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology*; D005312:Fetal Blood / Q000276:immunology*; D050990:GATA3 Transcription Factor / Q000096:biosynthesis; D020022:Genetic Predisposition to Disease; D006683:HLA-DQ Antigens / Q000235:genetics; D015804:HLA-DR4 Antigen / Q000235:genetics; D006650:Histocompatibility Testing; D006801:Humans; D007231:Infant, Newborn; D018793:Interleukin-13 / Q000096:biosynthesis; D012333:RNA, Messenger / Q000235:genetics; D054398:Receptors, CCR4; D019718:Receptors, CXCR4 / Q000096:biosynthesis / Q000097:blood; D019707:Receptors, Chemokine / Q000096:biosynthesis / Q000097:blood; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D015854:Up-Regulation / Q000276:immunology
C515354:CCR4 protein, human; D016207:Cytokines; D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; D006683:HLA-DQ Antigens; C109756:HLA-DQ8 antigen; D015804:HLA-DR4 Antigen; D018793:Interleukin-13; D012333:RNA, Messenger; D054398:Receptors, CCR4; D019718:Receptors, CXCR4; D019707:Receptors, Chemokine