Prenatal betamethasone protects against experimental Type 1 Diabetes by altering both immune system development and β-cells

Background. Environmental factors are crucial in the pathogenesis of type 1 diabetes (T1D). In this sense, betamethasone –a synthetic glucocorticoid administered to women at risk of preterm delivery to improve newborn survival– could alter the development of foetal immune system, influencing the risk of developing T1D in the offspring. The aim of this study was to determine the effect of prenatal betamethasone on T1D susceptibility. Methods. An incidence study was performed in the non–obese diabetic (NOD) mice offspring of betamethasone–treated pregnant females. Prenatal effect of betamethasone in lymphoid organ development and alterations in leukocyte subsets was determined after birth. T cell receptor Vβ repertoire was assessed by flow cytometry in the spleen from 6 weeks old mice. In vitro effects of betamethasone were evaluated in splenocytes and dendritic cells in terms of viability, phenotype and function. Additionally, the effect of betamethasone on β–cells was determined in the NOD β–cell line NIT–1 regarding growth, phenotype (flow cytometry), transcriptome (RT–qPCR) and insulin secretion (ELISA). Results. T1D incidence was reduced in the female offspring in the treated group (22%) when compared to sham (75%). Remarkably, betamethasone caused thymus hypotrophy and alteration in immune cells subsets in newborn mice. Regarding the Vβ T cell repertoire, a clearly decrease in the frequency of pathogenic T cells was observed. Betamethasone caused in vitro toxicity to resting lymphocytes and induced maturation–resistant dendritic cells, thus impairing autologous γδ T lymphocyte proliferation. Finally, betamethasone effects were detrimental for NIT–1 cell viability, arresting cell growth and reducing insulin secretion. Downregulation of CD44 membrane expression was induced in NIT–1 cell by betamethasone, together with upregulation of Ccl2, Cxcl2, Cd14 and Il22ra1 genes. Conclusion. Betamethasone has a protective effect against experimental T1D by altering the immune system response and potentially decreasing autoimmune recognition of β–cells. These results may have potential clinical relevance.