Recent results on the development of fetal immune system: Self, epigenetic regulation, fetal immune responses

Abstract

In vertebrates there are two major classes of defence systems acting against infectious microorganisms. Innate immune systems use constitutively expressed receptors recognizing conserved, repetitive structures on different classes of pathogens. Such unique molecules are usually absent from host cells, which ensures self-nonself discrimination. Adaptive immune systems ensure protective immunity by generating a vast repertoire of anticipatory receptors via somatic diversification of receptor encoding genes. Thus, in principle, adaptive immune systems are capable to recognize any unique molecular conformation (antigen). Antigen specificity, lymphoid tissue organization and memory are important innovations of adaptive immune systems. Because lymphoid cells can specifically recognize, in addition to the antigenic determinants of pathogens, self antigens (autoantigens) as well, multiple mechanisms evolved to curb destructive autoimmune reactions. In the absence of unique molecular signatures of self, a clonal selection process eliminates immature lymphocytes receiving strong signals via their receptors from certain surrounding (i.e. self) molecules in the central lymphoid organs (central tolerance). In the thymus, the nuclear protein AIRE (autoimmune regulator) switches on transcription of silent, tissue specific genes randomly, permitting presentation of the corresponding self antigens by medullary thymic epithelial cells to newly formed thymocytes (T cells). Cell fate decisions depend on the avidity of T cell receptor to the presented self antigen and antigen presentation (MHC) molecule: low affinity binding results in a positive selection (maturation to helper and cytotoxic T cells, migration to the periphery), whereas moderate-avidity interaction yields regulatory T cells that express the master transcription factor Foxp3 and display an anergic phenotype at the periphery. During pregnancy the maternal immune system adapts to the presence of fetal (paternal) alloantigens by activating multiple, redundant mechanisms of peripheral tolerance. On the course of B lymphocyte development epigenetic regulatory mechanisms coordinate the expression of lymphoid specific gene sets and ensure relocation of the recombining and non-recombining receptor gene segments (V, D, and J) to the suitable nuclear subcompartments. Pioneer transcription factors change the local and regional epigenetic marks of the genome, resulting in a new epigenome and transcriptional program. Epigenetic marks (DNA methylation, histone modifications, Polycomb/Trithorax complexes) can be transmitted from cell generation to cell generation (epigenetic memory). Induction of another master regulator or regulatory network by suitable signals may change, however, the epigenome, creating thereby a new cellular identity and phenotype. In humans, such processes do not result, however, in a fully developed immune system even at birth. This immaturity and immunodeficiency is compensated during intrauterine life by the transplacental passage of maternal high avidity IgG antibodies to the fetus and after birth by the complex antiinfective components present in human milk.