Author(s): Stephanie Glaesener 1, Christine Jaenke 1, Anika Habener 1,2, Robert Geffers 3, Petra Hagendorff 3, Katrin Witzlau 4, Esther Imelmann 5, Andreas Krueger 4,5, Almut Meyer-Bahlburg 1,2,*
The immaturity of the developing immune system in early life is reflected by an increased susceptibility to infections and decreased vaccination responses. Multiple factors within the innate and adaptive arm of the immune system have been identified contributing to this immaturity. Regarding humoral immunity, the neonate is initially protected by passively acquired maternal antibodies, although neonates are able to mount T cell-dependent and-independent immune responses [1-3]. However, neonatal antibody responses are delayed in onset, show decreased peak levels, are of shorter duration, and of lower antibody affinity [3-5]. The generation of high-affinity, class-switched, antibodies is a complex process relying on the interaction of T-, B-, and antigen-presenting cells (APCs). Thus, the immaturity of the neonatal immune system results from quantitative and qualitative deficiencies of many different cell types and their interplay with each other.
Neonatal APCs are found to be immature in terms of both number and function: The number of CD11c+ DC in mice and humans was reduced in neonates [6,7], and neonatal DC were deficient in upregulating costimulatory molecules including MHC-II, CD80, and CD86 upon stimulation, indicating their inability to fully activate antigen specific T and B cell responses [8-10].
Within the T cell compartment, lower numbers of effector-memory and follicular helper T cells were described, thereby impacting the generation of high-affinity antibodies . In addition, production of IL-4 and IL-21, as well as the expression of surface CD154 were shown to be reduced in activated cord blood T cells [12-15].
Regarding B cells, previous studies have shown that the peripheral B cell compartment notably differs between newborns and adults. Most importantly, CD27+ memory B cells are almost completely missing in neonates due to the lack of previous antigenic exposure [16-18]. Moreover, the CD27- naïve B cell fraction in neonates consists predominantly of transitional 1 and 2 (T1 and T2) B cells that are recent bone marrow emigrants , and only few mature naïve B cells. In addition, several phenotypic differences between neonatal and adult B cells have been described: Neonatal B cells have been shown to express different levels of various cell surface molecules, including CD22, CD40, CD80, CD86, and IgM [14,20-23]. Functional differences were identified regarding cytokine secretion, antigen presentation, and a decreased ability of neonatal B cells to class-switch [7,8,15,24,25].
Epigenetic mechanisms play important roles in developmental processes of many cell types. In particular, B cell development, activation and differentiation are regulated by miRNAs through repressing gene expression and impacting post-transcriptional processes [26-29]. Based on these data, impaired antibody responses in neonates seem to be the combined result of an altered microenvironment, a different composition of B cell subsets towards a more immature phenotype and B cell intrinsic factors. The latter are, especially in humans, still barely defined, and their influence remains vague. We therefore phenotypically, and functionally, characterized distinct B cell subpopulations...