Abstract
Abstract 1097
Dendritic cells (DCs) are antigen-presenting cells specialized to activate naïve T lymphocytes and initiate primary immune responses. The different classes of specific immune responses are driven by the biased development of pathogen-specific effector CD4+ T-cell subsets — that is, T helper 1 (Th1), Th2 and Th17 cells, that activate different components of cellular and humoral immunity. Th cell differentiation is critical for achieving proper immune responses, and imbalances in either the function or activity of these cell types are responsible for many immune diseases, including autoimmunity, cancer and allergy.
DCs reside in an immature state in many nonlymphoid tissues such as the skin, the intestine or airway mucosa which are under high exposure of pathogens and chemicals. DCs, which take up pathogens, develop their maturation processes, migrate to the T-cell areas of secondary lymphoid organs and interact with naïve T cells. TCR stimulation and co-stimulation allow naïve Th cells to develop into protective effector cells, normally accompanied by the high-level expression of selective sets of cytokines. The balance of these cytokines and the resulting class of immune response strongly depend on the conditions under which DCs are primed for the expression of the T-cell-polarizing molecules.
The ligands for many isoforms of toll-like receptors (TLRs), including certain nucleic acids, lipopolysaccharides (LPS) and fungus-derived glycoprotein molecules, alter the DC function, and induce Th1 differentiation in an antigen non-specific manner. In this process, IL-12 produced by DCs is clearly correlated with sensitization of Th1 lymphocytes in vitro and in vivo among the factors that have been shown to influence the Th1-Th2 balance.
On the other hand, DCs matured in the presence of prostaglandin E2 (PGE2), histamine, or forskolin induce the differentiation of naïve CD4+ T cells toward Th2 via the cyclic adenosine 3',5'-monophosphate (cAMP) cascade. In vitro assay systems have been established to evaluate Th1/Th2 adjuvant activities, using MLR and intracellular cAMP concentration of antigen-presenting cells.
The current study shows that mothers, whose children (n = 55) developed atopic dermatitis (AD) within 6 months after birth, often demonstrate a higher Th2 adjuvant activity in their milk, in comparison to those whose children did not develop such symptoms (figure). Such an activity was recovered in a liquid phase of mothers' milk and was eluted as a single fraction by reversed-phase HPLC. Further analysis of this fraction by mass spectrometry showed that signals originating from a factor with a molecular weight of 767.53 are observed, exclusively in milk with a high Th2 adjuvant activity. The mass is exactly that of Coenzyme A (CoA), and indeed, a low concentration of CoA exhibited Th2 adjuvant activity in vitro. Moreover, mesenteric lymph node non-T cells obtained from mice that were orally treated with CoA, led allogeneic naïve CD4+ T cells to differentiate into Th2. Furthermore, the oral administration of CoA induced rough skin, hyperplasia of the epidermis, hypergranulosis in the spinous layer and the thickening of the stratum in mice. These data collectively indicate that some of the patients with AD were exposed to mothers' milk carrying high Th2 adjuvant activity right after birth, which may be attributable to presence of CoA contained in the milk.
Disclosures:
No relevant conflicts of interest to declare.
Theoretical modeling reveals that regulatory T cells increase T-cell interaction with antigen-presenting cells for stable immune tolerance
