Evidence for immunological priming and increased frequency of CD4+ CD25+ cord blood T cells in children born to mothers with type 1 diabetes

Abstract

Maternal transmission of islet autoantibodies to children born to mothers with type 1 diabetes (T1D) has been shown to protect from autoantibodies and diabetes development later in life. However, the factors conferring disease protection are poorly understood. The aim of this study was to evaluate comparatively proinflammatory cytokines, autoantibodies and lymphocyte subsets in cord blood (CB) of children born to mothers with either T1D (n = 13), gestational diabetes (GDM) (n = 32) or healthy mothers (n = 81) in relation to transplacental passage of autoantibodies. The results are consistent with early priming of the fetal immune system only in children born to mothers with T1D. Levels of interleukin (IL)-1beta (P = 0.022), tumour necrosis factor (TNF)-alpha (P = 0.002) and IL-8 (P = 0.0012), as well as the frequency of CD4(+) CD25(+) T cells (P < 0.01) were significantly increased, and the increased levels correlated positively with anti-GAD65 autoantibody (GADA) levels. Moreover, CD4(+) CD25(+) T cells of children born to T1D mothers exhibited a more pronounced memory phenotype with increased CCR4 expression and down-regulation of CD62L. These data suggest that early activation of the fetal immune system as a consequence of maternal autoimmunity and transplacental passage of GADA may influence the generation and expansion of fetal regulatory T cells. This might induce an early antigen-specific immunological tolerance that could protect against T1D later in life.

Fig. 1

Flow cytometric analysis of cord blood lymphocytes. Cumulative analysis of the frequency of natural killer (NK) cells (defined by the expression of both CD16 and CD56 markers) (a), CD4⁺ CD25⁺ T cells (b), CD4⁺ CD25⁺ CCR4⁺ T cells (c) and CD4⁺ CD25⁺ CD62L^lo CCR4^hi (d) in cord blood of children born to healthy mothers (healthy, open squares), children born to mothers with gestational diabetes (GDM, open triangles) and with type 1 diabetes (T1D, open circles). Median values for each patient group are marked with a horizontal line. P-values < 0·0167 were considered significant after Bonferroni correction. *P < 0·05, **P < 0·0167, ***P < 0·001.

Fig. 2

Expression of forkhead box P3 (FOXP3) in cord blood (CB) and adult CD4⁺ CD25⁺ T cells. Representative flow cytometry analysis of CD4⁺ CD25⁺ T cells from cord and adult peripheral blood of healthy donors. Cells were stained with peridinin chlorophyll (PerCP)-labelled CD4, fluorescein isothiocyanate (FITC)-labelled CD25 and antigen-presenting cell (APC)-labelled FOXP3 monoclonal antibodies. The oval region depicting CD4⁺ T cells expressing high levels of CD25 in the dot plot from adult blood is the same used for the cord blood dot plot.