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Unique aspects of the perinatal immune system

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).

Abstract

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.

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Figure 1: Waves of immune cell ontogeny and effector or regulatory functions in early life disease.
Figure 2: Mechanisms of perinatal immune regulation.

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Acknowledgements

R.L.-M. and D.Z. are supported by an ANR grant (ANR 13-BSV3-0016) and by the Fondation pour la Recherche Médicale (grant number DEQ20120323719). R.L.-M. received funding from the French Government's Investissement d'Avenir program, Laboratoire d'Excellence 'Integrative Biology of Emerging Infectious Diseases' (grant number ANR-10-LABX-62-IBEID). X.Z. is supported by the National Basic Research Program of China (grant number 2014CB541904); National Natural Science Foundation of China (grant numbers 31270961 and 31470879); Interdisciplinary Innovation Team, External Cooperation Program (grant number GJHZ201312) and Key Project QYZDB-SSW-SMC036, and the Strategic Priority Research Program (grant number XDPB0303), Chinese Academy of Sciences.

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Glossary

Group B streptococcus

(GBS; also known as Streptocococcus agalactiae). The major cause of neonatal sepsis, a severe infection that affects preterm neonates, leading to severe inflammation and organ failure. The bacterium is transmitted from the mother upon delivery and the immune system has a crucial role in the outcome and the pathophysiological consequences of this infection.

Feto–maternal tolerance

Tolerance mechanisms that allow safe development of the fetus during pregnancy. They avoid fetal tissue rejection by the immune system of the mother and immune reactivity against non-inherited maternal antigens by the immune system of the fetus.

Innate lymphoid cells

(ILCs). Lymphoid cells derived from the common lymphoid progenitor that lack expression of an antigen receptor. ILCs have important roles in lymphoid tissue formation and homeostasis and also in linking innate and adaptive immune responses through effects on T helper cell polarization.

γδ T cells

T cells that express a T cell receptor consisting of a γ-chain and a δ-chain. These T cells are present in the intestinal epithelium as intraepithelial lymphocytes. γδ T cells are also present in the lungs, skin, liver and other tissue sites during inflammation. γδ T cells are thought to have an important role in innate immune responses.

Mucosa-associated invariant T cells

(MAIT cells). A population of innate-like lymphocytes that express an evolutionarily conserved invariant T cell receptor and are selected by the MHC class I-related molecule MR1. They are abundant in human blood, in the intestinal mucosa and in mesenteric lymph nodes, and can produce interferon-γ in response to various bacterial infections.

Pre-B cell receptor

A receptor that is formed at the surface of pre-B cells by the pairing of rearranged immunoglobulin heavy chains with surrogate light chains and the heterodimer of Igα and Igβ. Signalling by the pre-B cell receptor occurs in the absence of known ligands and is a crucial event in B cell development.

Pattern-recognition receptors

(PRRs). Host receptors that can sense pathogen-associated molecular patterns and initiate signalling cascades that lead to an innate immune response. PRRs can be membrane bound (such as Toll-like receptors) or soluble cytoplasmic receptors (such as NOD-like receptors).

Type I IFN

A family of cytokines that bind to the IFNα receptor (IFNAR) complex, which consists of IFNAR1 and IFNAR2 chains. The type I IFNs in humans are mainly IFNα, IFNβ and IFNλ and these IFNs mediate the inhibition of viral replication, activate natural killer cells and macrophages and increase antigen presentation to T cells during infections and during an immune response to tumour cells.

Tissue-resident memory T cells

Non-recirculating memory T cells that persist long-term in epithelial barrier tissues, including the gastrointestinal tract, lungs, skin and reproductive tract. They provide rapid on-site immune protection against known pathogens in peripheral tissues.

Immunodysregulation, polyendocrinopathy, enteropathy, X-linked syndrome

(IPEX syndrome). A disease caused by mutations in FOXP3 and characterized by refractory enteritis, autoimmune endocrinopathies (including type 1 diabetes), thyroiditis and allergy.

C-type lectin receptor

(CLR). A large family of receptors that bind glycosylated ligands and have multiple functions, such as cell adhesion, endocytosis, target recognition by natural killer cells and dendritic cell activation, as well as antigen capture and presentation.

Regulatory B cells

(Breg cells). Populations of B cells with immunosuppressive responses that control inflammation. These cells are most often associated with production of the immunosuppressive cytokine IL-10.

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Zhang, X., Zhivaki, D. & Lo-Man, R. Unique aspects of the perinatal immune system. Nat Rev Immunol 17, 495–507 (2017). https://doi.org/10.1038/nri.2017.54

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