Newborn infants are highly susceptible to infection. This defect in host defence has generally been ascribed to the immaturity of neonatal immune cells; however, the degree of hyporesponsiveness is highly variable and depends on the stimulation conditions1–7. These discordant responses illustrate the need for a more unified explanation for why immunity is compromised in neonates. Here we show that physiologically enriched CD71+ erythroid cells in neonatal mice and human cord blood have distinctive immunosuppressive properties. The production of innate immune protective cytokines by adult cells is diminished after transfer to neonatal mice or after co-culture with neonatal splenocytes. Neonatal CD71+ cells express the enzyme arginase-2, and arginase activity is essential for the immunosuppressive properties of these cells because molecular inhibition of this enzyme or supplementation with l-arginine overrides immunosuppression. In addition, the ablation of CD71+ cells in neonatal mice, or the decline in number of these cells as postnatal development progresses parallels the loss of suppression, and restored resistance to the perinatal pathogens Listeria monocytogenes and Escherichia coli8,9. However, CD71+ cell-mediated susceptibility to infection is counterbalanced by CD71+ cell-mediated protection against aberrant immune cell activation in the intestine, where colonization with commensal microorganisms occurs swiftly after parturition10,11.Conversely, circumventing such colonization by using antimicrobials or gnotobiotic germ-free mice overrides these protective benefits. Thus, CD71+ cells quench the excessive inflammation induced by abrupt colonization with commensal microorganisms after parturition. This finding challenges the idea that the susceptibility of neonates to infection reflects immune-cell-intrinsic defects and instead highlights processes that are developmentally more essential and inadvertently mitigate innate immune protection. We anticipate that these results will spark renewed investigation into the need for immunosuppression in neonates, as well as improved strategies for augmenting host defence in this vulnerable population.

Neutrophils modulated antigen presentation following immunization with antigens in complete or incomplete Freund's adjuvant or alum. The neutrophils had an important negative role in the CD4 T cell and B cell responses to three protein antigens, hen-egg white lysozyme (HEL), ovalbumin (OVA) and listeriolysin O (LLO). In their absence (by depleting with antibodies for only the first twenty-four hours, or using genetically neutropenic mice), the cellular responses increased several fold. The CD8 response was not affected or slightly decreased. Competition for antigen between the presenting cells and the neutrophils, as well as an effect on the response to antigen-bearing dendritic cells (DC) was documented. Neutrophils entered the draining lymph nodes, rapidly and for a brief period of several hours, localizing mainly to the marginal sinus and superficial cortex. There they established brief contacts with DC and macrophages. Moreover, neutrophils imprinted on the quality of the subsequent DC-T cell interactions, despite no physical contacts with them: by intravital microscopy, the clustering of antigen-specific T cells and DC was improved in neutropenic mice. Thus, neutrophils are obligate cells that briefly enter sites of immunization and set the level of antigen presentation: a brief depletion may have a considerably positive impact on vaccination.

SUMMARY Exposure to maternal tissue during in utero development imprints tolerance to immunologically foreign non-inherited maternal antigens (NIMA) that persists into adulthood. The biological advantage of this tolerance, conserved across mammalian species, remains unclear. Here we show that maternal cells which establish microchimerism in female offspring during development promote systemic accumulation of immune suppressive regulatory T cells (Tregs) with NIMA specificity. NIMA-specific Tregs expand during pregnancies sired by males expressing alloantigens with overlapping NIMA specificity, thereby averting fetal wastage triggered by prenatal infection and non-infectious disruptions of fetal tolerance. Therefore, exposure to NIMA selectively enhances reproductive success in second-generation females carrying embryos with overlapping paternally inherited antigens. These findings demonstrate that genetic fitness, canonically thought to be restricted to Mendelian inheritance, is enhanced in female placental mammals through vertically transferred maternal cells that promote conservation of NIMA and enforce cross-generational reproductive benefits.

In antigen-presenting cells (APC), presentation by class II-MHC molecules of the chemically-dominant peptide from the protein hen egg white lysozyme (HEL) generates different conformational isomers of the peptide-MHC II complexes (pMHC). Type B pMHCs are formed in early endosomes from exogenous peptides in the absence of H2-DM, while in contrast, type A pMHC complexes are formed from HEL protein in late vesicles after editing by H2-DM. Thus, H2-DM edits off the more unstable pMHC complexes, which are not presented from HEL. Here we show that type B pMHC complexes were presented from HEL protein only after stimulation of dendritic cells (DC) with TLR ligands or type I IFN. Type I IFN contributed to most TLR ligand-induced type B pMHC generation as presentation decreased in DC lacking the receptor for type I interferons (IFNAR1-/-). In contrast, presentation of type A pMHC from HEL and from peptide was minimally affected by TLR ligands. The relative effectiveness of CD8α+ DC or CD8α- DC in presenting type B pMHC complexes varied depending on the TLR-ligand used. The mechanisms of generation of type B pMHC from HEL protein with TLR stimulation did not involve H2-DM or release of peptides. DC from H2-DM-deficient mice in the presence of TLR-ligands presented type B pMHC. Such DC showed a slight enhancement of HEL catabolism, but peptide-release was not evident. Thus, TLR ligands and type I IFN alter the pathways of presentation by class II MHC molecules of DC such that type B pMHCs are generated from protein antigen.

The primary benefits of in utero hematopoietic cellular transplantation (IUHCT) arise from transplanting curative cells prior to the immunologic maturation of the fetus. However, this approach has been routinely successful only in the treatment of congenital immunodeficiency diseases that include an inherent NK cell deficiency despite the existence of normal maternal immunity in either setting. These observations raise the possibility that fetal NK cells function as an early barrier to allogeneic IUHCT. Herein, we summarize the findings of previous studies of prenatal NK cell allospecific tolerance in mice and in humans. Cumulatively, this new information reveals the complexity of the fetal immune response in the setting of rejection or tolerance and illustrates the role for fetal NK cells in the final endorsement of allospecific prenatal tolerance.