Reduced expression of CCR4 on cord blood T lymphocytes in neonates at genetic risk of type 1 diabetes

• In type 1 diabetes the T cell polarization and expression of chemokine receptors have been reported to be aberrant. We asked whether these aberrancies are present already at birth in neonates carrying HLA risk haplotypes for type 1 diabetes.Cord blood (CB) samples were obtained from neonates taking part in the Trial to Reduce IDDM in Genetically at Risk (TRIGR) and the Finnish Dietary Intervention Trial for Prevention of Type 1 Diabetes (FINDIA) studies and were screened for type 1 diabetes-associated HLA risk genotypes (HLA DR3-DQ2 and/or DR4-DQ8 without protective alleles). CB lymphocytes were stimulated with phytohemagglutinin (PHA) in type 1 (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, cytokines were analyzed with ELISA, and transcription factors were analyzed using real-time RT-PCR.When compared to the control group, neonates carrying alleles DQ2/DQ8 or DQ8 showed reduced percentage of CD4 T cells expressing CCR4 and lower levels of CCR4 mRNA after culture of CB lymphocytes in type 2 cytokine environment. In addition, these neonates had significantly lower secretion of iL-13 and expression of GATA-3 after culture of CB lymphocytes in type 2 cytok:ine environment in comparison to neonates with no increased genetic risk of type 1 diabetes.These results suggest aberrancies in the in vitro regulation of type 2 immune responses in children with increased genetic risk of type 1 diabetes when compared to neonates without HLA risk haplotypes suggesting that the HLA genotype may affect the T cell polarization already at birth. Aberrant induction ofT cell polarization may contribute to development of autoimmunity later in life.

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