COM MU N I T Y CO R N E R
A new unexpected twist in newborn immunity
Russell Kightley / Science Source
© 2014 Nature America, Inc. All rights reserved.
What causes the often poor responses of the newborn immune system to pathogens and vaccines remains a mystery and poses a challenge in the clinic for tackling infections in infants. A new study by Elahi et al.1 describes an enriched population of nonimmune cells in neonates that exert an immunosuppressive role to reduce the excessive inflammation that would otherwise occur upon commensal colonization after birth. The result of this developmental process is an increased susceptibility to pathogens and reduced immune protection. We asked three experts about the potential therapeutic implications of the findings and how the results of the study contribute to our understanding of neonatal vulnerability.
1. Elahi, S. et al. Immunosuppressive CD71 erythroid cells compromise neonatal host defence against infection. Nature 504, 158–162 (2013). 2. Adkins, B. Neonatal immunology: responses to pathogenic microorganisms and epigenetics reveal an “immunodiverse” developmental state. Immunol. Res. 57, 246–257 (2013). 3. Levy, O. Innate immunity of the newborn: basic mechanisms and clinical correlates. Nat. Rev. Immunol. 7, 379–390 (2007). 4. Mold, J.E. et al. Fetal and adult hematopoietic stem cells give rise to distinct T cell lineages in humans. Science 330, 1695–1699 (2010). 5. Pettengill, M. et al. Soluble ecto-5ʹ-nucleotidase (5ʹNT), alkaline phosphatase, and adenosine deaminase (ADA1) activities in neonatal blood favor elevated extracellular adenosine. J. Biol. Chem. 288, 27315–27326 (2013). 6. Kollmann, T.R., Levy, O., Montgomery, R.R. & Goriely, S. Innate immune function by Toll-like receptors: distinct responses in newborns and the elderly. Immunity 37, 771–783 (2012). 7. Levy, O. & Netea, M.G. Innate immune memory: implications for development of pediatric immunomodulatory agents and adjuvanted vaccines. Pediatr. Res. doi:10.1038/pr.2013.214 (6 November 2013). 8. Matamoros, S. et al. Development of intestinal microbiota in infants and its impact on health. Trends Microbiol. 21, 167–173 (2013). 9. Lathrop, S.K. et al. Peripheral education of the immune system by colonic commensal microbiota. Nature 478, 250–254 (2011). 10. Hooper, L.V. et al. Interactions between the microbiota and the immune system. Science 336, 1268–1273 (2012).
Becky Adkins In the latter part of the twentieth century, neonates were often referred to as immunodeficient, but research over the past 15 years has shown that neonatal immune responses defy this simple categorization. Neonates actually seem to embody the ultimate diversity in immune responsiveness, with responses ranging from very weak to very strong. Although robust responses can be observed, they are the exception, and often responses are weak and associated with poor vaccine outcomes and extreme susceptibility to infection. Understanding the cellular and molecular regulation of the poorly protective responses in neonates is a major challenge, and a better knowledge of the underlying immune mechanisms will allow the development of interventional strategies for enhancing neonatal immune responses in all settings. There is mounting evidence that the reduced responsiveness may be attributed to multiple factors, including developmentally regulated epigenetic processes2, negative regulators in plasma3 and the preferential development of T regulatory cells in early life relative to adulthood4. A recent paper by Elahi et al.1 adds another important negative regulatory mechanism by showing that both neonatal mouse spleen and human umbilical cord blood contain high proportions of CD71+ erythroid-lineage cells with immune-suppressive properties. Small numbers of phenotypically similar cells were also detected in adult mice and humans; however, the adult mouse CD71+ cells did not show immunosuppressive properties, suggesting that the negative regulatory function of this population may be specific to early development. Depletion of these cells led to enhanced innate responses of mouse neonatal cells to Listeria monocytogenes in vitro and increased resistance to bacterial growth in mouse neonates in vivo. Because the suppressive effects of these cells arose from their expression of arginase-2 and, strikingly, supplementation
Ofer Levy The World Health Organization susceptibility by impairing proinflamestimates that every year over 2 matory or T helper 1 (TH1)-polarizing million infants responses in early under the age of life, which are “This new mechanism 6 months die as a thought to be neclimits microbe-induced essary for fetomaresult of infection. The recent study ternal tolerance production of TH1 by Elahi et al. 1 during gestation cytokines, and its and to avoid potenhas defined a surtially overexuberprising additional selective and targeted ant inflammation mechanism that reversal may boost during microbial may contribute to colonization after the susceptibility to neonatal immunity to birth 6 . The new invasive infection enhance clearance of with intracellular study now identipathogens such as fies the existence of infection.” L. monocytogenes, nucleated CD71Mycobacterium tuberculosis and her- positive erythroid cells that are elepes simplex virus. Certain cellular and vated in neonatal peripheral blood soluble factors5 seem to promote this during the first weeks of life and that VOLUME 20 | NUMBER 1 | JANUARY 2014 NATURE MEDICINE
COM MU N I T Y CO R N E R
© 2014 Nature America, Inc. All rights reserved.
Alexander G Betz with arginine overcame immune suppression by these cells in vitro, transient arginine supplementation may be clinically effective in infants to potentially boost resistance during acute infection and enhance responses to inert vaccines. Interestingly, these CD71+ erythroid cells seem to be protective against inflammation during commensal colonization after birth, which sheds light into how neonates avoid excessive inflammation that could negatively affect normal postnatal development. The discovery of these cells as negative regulators of neonatal immune responses leads to additional questions, such as how they are overcome or circumvented in those instances in which neonates mount adult-like responses to pathogens. This is most clear in experimental settings where neonatal and adult responses can be directly compared as has been shown for oral Yersinia enterocolitica and pulmonary Chlamydia muridarum infection of neonatal mice2. Similarly, what processes overwhelm these regulatory mechanisms in cases of extreme pathological inflammation, such as neonatal sepsis? Lastly, the authors infected the mouse neonates with L. monocytogenes by intraperitoneal injection, whereas neonates encounter the vast majority of infectious agents at mucosal surfaces, notably the lungs and intestines. Although the CD71+ population may be important in dampening inflammation upon systemic infection or in response to commensal colonization in the intestines, this regulatory population may be overwhelmed by regional infection with pathogenic microorganisms. Therefore, it remains to be determined whether and how these mechanisms regulate inflammation in response to pathogens at mucosal surfaces.
Professor of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, Florida, USA. COMPETING FINANCIAL INTERESTS The author declares no competing financial interests.
express arginase-2, an enzyme that impairs innate immune responses, including T H 1-polarizing tumor necrosis factor-a (TNF-a) production to a range of microbial stimuli. Depleting CD71 cells from mouse splenocytes or human mononuclear cell fractions in vitro and from mice in vivo enhanced TNF-a responses induced by L. monocytogenes and substantially improved the ability of mice to clear infection. Administration of an anti-CD71 antibody resulted in spontaneous TNF-a production by mouse phagocytes in the intestine, a tissue that is rapidly colonized with a broad range of bacteria shortly after birth. Because treatment with antibiotics or under germ-free conditions did not cause the same effects, it seems that CD71+ cells function to reduce inflammation in response to early-life microbial colonization at the cost of increased susceptibility to infection.
Overall, early-life innate immune ontogeny is highly regulated, consistent with its crucial role in both shortand long-term host defense7. This new mechanism limits microbe-induced production of TH1 cytokines, and its selective and targeted reversal may boost neonatal immunity to enhance clearance of infection. Our growing appreciation of the distinct regulation of neonatal and infant immunity may inform new approaches to prevent and treat infectious, inflammatory and/or immunologic diseases of early life, potentially benefitting millions. Staff Physician, Division of Infectious Diseases, Boston Children’s Hospital, and Associate Professor at Harvard Medical School, Boston, Massachusetts, USA. COMPETING FINANCIAL INTERESTS The author declares competing financial interests: details are available in the online version of the paper (doi:10.1038/nm.3488).
NATURE MEDICINE VOLUME 20 | NUMBER 1 | JANUARY 2014
The colonization of an infant with a diverse variety of bacteria is crucial for the normal development of the newborn’s commensal microbiota8; however, the sudden transition from a sterile in utero environment to extensive colonization with commensal bacteria is tricky. The infant’s fledgling immune system is suddenly faced with a massive influx of microbes, yet a response against these new arrivals would be counterproductive and potentially harmful. The discovery of the temporarily enriched pool of immunosuppressive CD71+ cells by Elahi et al.1 explains how the newborn’s immune system copes with this surge of proinflammatory signals, allowing it to adapt to its newfound allies. The interaction between the immune system and the gut microbiota has an important role in maintaining longterm health. The commensal microbiota actively educates the immune system by shaping the balance between pro- and anti-inflammatory mechanisms 9 and helps to defend the host from pathogen colonization by competing for resources and creating an antagonistic environment. Interference with this delicate equilibrium between host immunity and commensal bacteria can have disastrous consequences for long-term health, leading to allergies, autoimmunity and even metabolic syndrome10.
“[Necrotizing enterocolitis in premature babies] might give us a glimpse of what would happen without the modulation by CD71+ cells.” The greater susceptibility of neonates to microbial infections shown in this study seems to be a side effect of the CD71 + cell–mediated immunosuppression that allows colonization by commensal bacteria. The transfer of antibodies from mother to baby through colostrum and milk not only counteracts this vulnerability but also is likely to shape the composition of the gut microbiota. An immune response against commensals in the neonate would interfere with establishing a symbiotic equilibrium. It has been hypothesized that the hyperinflammation leading to the destruction of the gut observed in necrotizing enterocolitis in premature babies might occur because the immune system of the premature baby over-reacts to the influx of bacteria, as the immunosuppressive CD71+ cells have yet to develop. This devastating disease might give us a glimpse of what would happen without the modulation by CD71+ cells. Program leader at the Medical Research Council Laboratory of Molecular Biology, Cambridge, UK. COMPETING FINANCIAL INTERESTS The author declares no competing financial interests.