Regulation of innate and acquired immunity in infants by commensal bacteria

Abstract: The incidence of atopic diseases in children is steadily increasing in the industrialised world along with an improved hygienic lifestyle. The gastrointestinal flora may be of specific importance for the proper maturation of the immune system and for the induction of tolerance, in which CD25+ regulatory T cells (Tregs) play a crucial role. The aim of this study was to examine how neonatal innate immune cells respond to stimulation with commensal gut bacteria and how intestinal colonisation affects the in vivo development of acquired immunity in children in a prospective study.Mononuclear cells, purified monocytes and monocyte-derived dendritic cells (DC) were stimulated in vitro with gut bacteria. We found that commensal bacteria induced at least as high levels of IL-12, TNF, IL-10 and IL-6 from neonatal mononuclear cells as from adult cells. Gram-positive bacteria induced higher levels of IL-12 and TNF from monocytes than did gram-negative strains, but during the differentiation into DC the response to commensal gram-positive bacteria were dramatically reduced. Sixty-four children were recruited to the prospective study and blood samples were obtained at birth, at 3-5 days, 4 months and 18 months of age. The proportion and absolute count of T cell and B cell populations and CD25+ Tregs were analysed by flow cytometry. Mononuclear cells were stimulated with allergens and bacteria and analysed for cytokine production. We found that the proportion and the number of peripheral CD4+ T cells and CD25+ Tregs increased during the first days of life. When correlating the development of lymphocyte populations to intestinal colonisation, we found that the children colonised with superantigen-producing Staphylococcus aureus early in life had increased their peripheral numbers of CD25+ Tregs from birth to 4 months of life. Furthermore, mononuclear cells from children who were colonised with toxin-producing S. aureus did generally not produce IL-13 and IL-5 in response to stimulation with birch allergen.In conclusion, neonatal innate cells potently respond to commensal gut bacteria, which may be important for the maturation of the immune system. Gram-positive and gram-negative bacteria differentially affect monocytes and DC, which may have implications for how commensal bacteria regulate mucosal and systemic immunity. Colonisation with superantigen-producing S. aureus early in life induces an expansion of CD25+ Tregs and prevents Th2-responses to allergens. Thus, subjection to a strong stimulus during infancy may decrease the risk to develop allergy.