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Metabolism and gut microbiota are essential for newborn health, influencing immune function, energy balance, and growth. Breast milk provides IgA, crucial for shaping gut microbiota in infants. In non-breastfed newborns, we observe the presence of IgM antibodies that can recognize various bacteria, influence bacterial clustering, and alter bacterial metabolism, such as carbon source utilization in vitro within small bacterial communities. Based on these findings, we developed a monoclonal IgM, M291, derived from a newborn-B cell, which mimics naturally occurring antibodies and could serve as a surrogate tool to modulate intestinal bacterial functions and metabolism. Oral administration of M291 alters the metabolome of germ-free mice colonized with a defined bacterial consortium or an infant gut microbiota, by modulating the bacterial transcriptome, while maintaining microbial abundance and diversity. This study establishes proof of concept for the design and application of newborn-derived antibodies to modulate microbial and host metabolism, including lipid metabolism and bile acid secretion, without significantly altering microbiota composition. Here, the authors characterize a newborn-derived monoclonal IgM, showing it influences bacterial clustering, gene expression, and metabolic activity, thereby modulating gut bacterial functions and host metabolism without altering microbiota composition.

Neonates are highly susceptible to infectious diseases and defective antiviral pDC immune responses have been proposed to contribute to this phenomenon. Isolated cord blood pDCs innately responded to a variety of TLR7 and TLR9 dependent viruses, including influenza A virus (IAV), human immunodeficiency virus (HIV) or herpes-simplex virus (HSV) by efficiently producing IFN-α, TNF-α as well as chemokines. Interestingly, following activation by CpGA, but not viruses, cord pDCs tend to survive less efficiently. We found that a hallmark of pDCs in neonates is an extended CD2+pDCs compartment compared to adult pDCs without affecting the antiviral IFN-α response. Within CD2+pDCs, we identified a subpopulation expressing CD5 and responsible for IL-12p40 production, however this population is significantly decreased in cord blood compared to adult blood. Therefore, neonatal pDCs clearly display variation in phenotype and subset composition, but without major consequences for their antiviral responses.

Respiratory syncytial virus (RSV) is the prevalent pathogen of lower respiratory tract infections in children. The presence of neonatal regulatory B lymphocytes (nBreg) has been associated with a poor control of RSV infection in human newborns and with bronchiolitis severity. So far, little is known about how nBreg may contribute to neonatal immunopathology to RSV. We tracked nBreg in neonatal BALB/c mice and we investigated their impact on lung innate immunity, especially their crosstalk with alveolar macrophages (AMs) upon RSV infection. We showed that the colonization by nBreg during the first week of life is a hallmark of neonatal lung whereas this population is almost absent in adult lung. This particular period of age when nBreg are abundant corresponds to the same period when RSV replication in lungs fails to generate a type-I interferons (IFN-I) response and is not contained. When neonatal AMs are exposed to RSV in vitro, they produce IFN-I that in turn enhances IL-10 production by nBreg. IL-10 reciprocally can decrease IFN-I secretion by AMs. Thus, our work identified nBreg as an important component of neonatal lungs and pointed out new immunoregulatory interactions with AMs in the context of RSV infection.

The Tn antigen (GalNAcα- O -Ser/Thr) is a well-established tumor-associated marker which represents a good target for the design of anti-tumor vaccines. Several studies have established that the binding of some anti-Tn antibodies could be affected by the density of Tn determinant or/and by the amino acid residues neighboring O -glycosylation sites. In the present study, using synthetic Tn-based vaccines, we have generated a panel of anti-Tn monoclonal antibodies. Analysis of their binding to various synthetic glycopeptides, modifying the amino acid carrier of the GalNAc(*) (Ser* vs Thr*), showed subtle differences in their fine specificities. We found that the recognition of these glycopeptides by some of these MAbs was strongly affected by the Tn backbone, such as a S*S*S* specific MAb (15G9) which failed to recognize a S*T*T* or a T*T*T* structure. Different binding patterns of these antibodies were also observed in FACS and Western blot analysis using three human cancer cell lines (MCF-7, LS174T and Jurkat). Importantly, an immunohistochemical analysis of human tumors (72 breast cancer and 44 colon cancer) showed the existence of different recognition profiles among the five antibodies evaluated, demonstrating that the aglyconic part of the Tn structure (Ser vs Thr) plays a key role in the anti-Tn specificity for breast and colon cancer detection. This new structural feature of the Tn antigen could be of important clinical value, notably due to the increasing interest of this antigen in anticancer vaccine design as well as for the development of anti-Tn antibodies for in vivo diagnostic and therapeutic strategies.

Key Points Specific effector and regulatory players have a role in ineffective immunity and the dysregulation of inflammation in diseases that affect newborns and infants. To better understand the infections and diseases that affect newborns, host–microorganism interactions should be investigated in the context of age-specific immune regulation. Disruption of the delicate balance between hypo- and hyperinflammation in the context of infection can lead rapidly to life-threatening clinical situations, highlighting the need to better understand mechanisms of inflammation in early life. Many regulatory cell types — including regulatory T cells, regulatory B cells and myeloid-derived suppressor cells — are implicated in the control of inflammation, but they limit immunity to infection in newborns to permit safe development of the fetus and to allow colonization of the commensal microbiota to be tolerated. In the absence of any infection, transplacental antigen transfer occurs during pregnancy, and this can lead to in utero priming of fetal T cells in response to allergens or vaccines. The perinatal environment supports type 2 immune responses to favour vital functions and tissue homeostasis and remodelling; however, this response can be reshaped in vivo (for example, by vaccination). Why are newborns more vulnerable to infection? Here, the authors explain that it is not the immaturity of the immune system per se, but the unique regulation of immune responses in early life that limits immunity to infection yet allows safe development in utero and the accommodation of microbial colonization at birth. The early stages of life are associated with increased susceptibility to infection, which is in part due to an ineffective immune system. In the context of infection, the immune system must be stimulated to provide efficient protection while avoiding insufficient or excessive activation. Yet, in early life, age-dependent immune regulation at molecular and cellular levels contributes to a reduced immunological fitness in terms of pathogen clearance and response to vaccines. To enable microbial colonization to be tolerated at birth, epigenetic immune cell programming and early life-specific immune regulatory and effector mechanisms ensure that vital functions and organ development are supported and that tissue damage is avoided. Advancement in our understanding of age-related remodelling of immune networks and the consequent tuning of immune responsiveness will open up new possibilities for immune intervention and vaccine strategies that are designed specifically for early life.

Pathogen-specific immune memory develops subsequent to primary exposure to antigen, mainly in the context of infection or vaccination to provide protection. Although a safe fetal life requires a tolerogenic environment in order to circumvent unnecessary inflammatory responses, it needs to be prepared in utero to face the microbial environment outside the womb. The possibility of immune memory generation in the fetus would help such transition providing protection in early life. This requires fetal T cell exposure to foreign antigens presented by dendritic cells. There are evidences of fetal T cell priming in several cases of congenital infections or in uninfected children born of infected mothers. Fetal T cell memory seems to arise also without any reported infection during pregnancy. Such memory T cells display various effector functions, including Th1, Th2, or Th17 profiles, raising the issue of benefits and risks for postnatal life when considering maternal vaccination, susceptibility to infection, or environmental allergen sensitization.

IL-10-producing B cells are a new family of regulatory cells that control the immune responses at the innate and adaptive levels. In the neonatal context, we described that such regulatory B cells (Bregs) dampened immune responses to adjuvants and vaccines. For a long time, it has been postulated that immune system immaturity was responsible for this phenomenon; however, increasing evidence indicates that immune regulation rather than immaturity is at work. We demonstrated that innate CD5 Bregs negatively control innate inflammation and dendritic cell functions in neonatal mice by producing high amounts of IL-10 following Toll-like receptor triggering. These immune regulatory mechanisms can protect from lethal inflammation, control the development of autoimmune diseases, such as experimental autoimmune encephalomyelitis, and could be evoked in chronic inflammatory states, such as in cancer.

Malignant transformations are often associated with aberrant glycosylation processes that lead to the expression of new carbohydrate antigens at the surface of tumor cells. Of these carbohydrate antigens, the Tn antigen is particularly highly expressed in many carcinomas, especially in breast carcinoma. We designed MAG-Tn3, a fully synthetic vaccine based on three consecutive Tn moieties that are O -linked to a CD4 + T cell epitope, to induce anti-Tn antibody responses that could be helpful for therapeutic vaccination against cancer. To ensure broad coverage within the human population, the tetanus toxoid-derived peptide TT830-844 was selected as a T-helper epitope because it can bind to various HLA-DRB molecules. We showed that the MAG-Tn3 vaccine, which was formulated with the GSK proprietary immunostimulant AS15 and designed for human cancer therapy, is able to induce an anti-Tn antibody response in mice of various H-2 haplotypes, and this response correlates with the ability to induce a specific T cell response against the TT830-844 peptide. The universality of the TT830-844 peptide was extended to new H-2 and HLA-DRB molecules that were capable of binding this T cell epitope. Finally, the MAG-Tn3 vaccine was able to induce anti-Tn antibody responses in cynomolgus monkeys, which targeted Tn-expressing tumor cells and mediated tumor cell death both in vitro and in vivo. Thus, MAG-Tn3 is a highly promising anticancer vaccine that is currently under evaluation in a phase I clinical trial.

Background. The elicitation of T-helper type 1 (Th1) cellular immunity to eradicate intracellular pathogens is a challenging task because of the interleukin 12 (IL-12) deficit observed in early infancy. Methods. Screening cord blood responses to various pediatrie vaccines and Toll-like receptor (TLR) agonists for innate responses and CD4⁺ T-cell differentiation. Results. We identified that nonadjuvanted inactivated trivalent influenza vaccine (TIV) was able to cosignai T cells for the production of interferon γ (IFN-γ) in a neonatal setting. This process includes the mobilization of neonatal plasmacytoid dendritic cells (pDCs) as antigen-presenting cells (APCs) that efficiently engage Th1 cells in an IL-12-independent but type I IFN-dependent manner. In addition, cord blood pDCs efficiently cross-presented antigen to CD8⁺ T cells. Importantly, activation by TIV mainly requires TLR7; however, R848/TLR7- and CpGB/TLR9-activated pDCs, which poorly produced IFN-α, induce neonatal Th2 responses. Conclusions. TLR pathway engagement in pDCs is necessary but not sufficient for a successful neonatal Th1 outcome. We provide evidence of a mature and functional neonatal immune system at the level of APCs and T cells and propose to implement the IFN-α/IFN-γ axis in pediatric vaccination as a surrogate for the defective IL-12/IFN-γ axis.

The neonatal intestinal immune system is still undergoing development at birth, leading to a higher susceptibility to mucosal infections. In this study, we investigated the effect of poly(I:C) on controlling enteric infection by the protozoan Cryptosporidium parvum in neonatal mice. After poly(I:C) administration, a rapid reduction in parasite burden was observed and proved to be dependent on CD11c(+) cells and TLR3/TRIF signaling. Protection against C. parvum required additional signals provided by the gut flora through TLR5 and MyD88 signaling. This cooperation gave rise to higher levels of expression of critical mutually dependent cytokines such as interleukin 12p40 and type 1 and type 2 interferons, the last 2 being known to play a key role in the elimination of infected enterocytes. Our findings demonstrate in neonatal mice how gut flora synergizes with poly(I:C) to elicit protective intestinal immunity against an intracellular pathogen.