Letter | Published:

Immunosuppressive CD71+ erythroid cells compromise neonatal host defence against infection

Nature volume 504, pages 158162 (05 December 2013) | Download Citation


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 conditions1,2,3,4,5,6,7. 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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    , , & Innate immune function by Toll-like receptors: distinct responses in newborns and the elderly. Immunity 37, 771–783 (2012)

  2. 2.

    et al. Challenges in infant immunity: implications for responses to infection and vaccines. Nature Immunol. 12, 189–194 (2011)

  3. 3.

    , & Neonatal immunity: faulty T-helpers and the shortcomings of dendritic cells. Trends Immunol. 30, 585–591 (2009)

  4. 4.

    , & Neonatal adaptive immunity comes of age. Nature Rev. Immunol. 4, 553–564 (2004)

  5. 5.

    et al. Neonatal innate TLR-mediated responses are distinct from those of adults. J. Immunol. 183, 7150–7160 (2009)

  6. 6.

    et al. Selective impairment of TLR-mediated innate immunity in human newborns: neonatal blood plasma reduces monocyte TNF-α induction by bacterial lipopeptides, lipopolysaccharide, and imiquimod, but preserves the response to R-848. J. Immunol. 173, 4627–4634 (2004)

  7. 7.

    Neonatal and early life vaccinology. Vaccine 19, 3331–3346 (2001)

  8. 8.

    & Listeriosis. J. Am. Med. Assoc. 261, 1313–1320 (1989)

  9. 9.

    , & Neonatal infectious diseases: evaluation of neonatal sepsis. Pediatr. Clin. North Am. 60, 367–389 (2013)

  10. 10.

    & The development of the bacterial flora in normal neonates. J. Med. Microbiol. 14, 51–62 (1981)

  11. 11.

    Implantation and development of the gut flora in the newborn animal. Ann. Rech. Vet. 14, 354–359 (1983)

  12. 12.

    , , , & Alteration of non-specific resistance to infection with Listeria monocytogenes. Infection 16 (suppl. 2). S112–S117 (1988)

  13. 13.

    & Immunological tolerance during fetal development: from mouse to man. Adv. Immunol. 115, 73–111 (2012)

  14. 14.

    Evidence that tumor necrosis factor has an important role in antibacterial resistance. J. Immunol. 143, 2894–2899 (1989)

  15. 15.

    , & Endogenous tumor necrosis factor (cachectin) is essential to host resistance against Listeria monocytogenes infection. Infect. Immun. 56, 2563–2569 (1988)

  16. 16.

    , , & Immune and inflammatory responses in TNF α-deficient mice: a critical requirement for TNF α in the formation of primary B cell follicles, follicular dendritic cell networks and germinal centers, and in the maturation of the humoral immune response. J. Exp. Med. 184, 1397–1411 (1996)

  17. 17.

    & Regulation of immune responses by l-arginine metabolism. Nature Rev. Immunol. 5, 641–654 (2005)

  18. 18.

    Arginine: master and commander in innate immune responses. Sci. Signal. 3, pe27 (2010)

  19. 19.

    Nucleated red blood cells in the fetus and newborn. Arch. Dis. Child. Fetal Neonatal Ed. 84, F211–F215 (2001)

  20. 20.

    , & Murine neonates develop vigorous in vivo cytotoxic and TH1/TH2 responses upon exposure to low doses of NIMA-like alloantigens. Blood 112, 1530–1538 (2008)

  21. 21.

    et al. Rac1 and Rac2 GTPases are necessary for early erythropoietic expansion in the bone marrow but not in the spleen. Haematologica 95, 27–35 (2010)

  22. 22.

    et al. Arginase release from red blood cells: possible link in transfusion induced immune suppression? Shock 16, 113–115 (2001)

  23. 23.

    , , , & Suppression of adaptive immunity to heterologous antigens during Plasmodium infection through hemozoin-induced failure of dendritic cell function. J. Biol. 5, 5 (2006)

  24. 24.

    et al. Immunosuppressive effects of red blood cells on monocytes are related to both storage time and storage solution. Transfusion 52, 794–802 (2012)

  25. 25.

    & Is there a direct role for erythrocytes in the immune response? Vet. Res. 42, 89 (2011)

  26. 26.

    , , , & Innate immune activation during Salmonella infection initiates extramedullary erythropoiesis and splenomegaly. J. Immunol. 185, 6198–6204 (2010)

  27. 27.

    , & Malaria: a haematological disease. Hematology 17, 106–114 (2012)

  28. 28.

    et al. Ontogeny of erythroid gene expression. Blood 121, e5–e13 (2013)

  29. 29.

    , , & Reciprocal interactions of the intestinal microbiota and immune system. Nature 489, 231–241 (2012)

  30. 30.

    et al. Commensal bacteria calibrate the activation threshold of innate antiviral immunity. Immunity 37, 158–170 (2012)

Download references


We thank D. Haslam, M. Hostetter, L. Muglia, J. Whitsett and C. Wilson for discussions, J. Mortensen for help with anaerobic cultures, and K. Eaton, C. Schray and the University of Michigan Unit for Laboratory Animal Medicine for providing germ-free mice. We thank the Mount Auburn OB-GYN associates, OB-GYN residents, and the University and Christ Hospital labour and delivery nursing staff for collecting cord blood, the Cell Processing and Manipulation Core for obtaining peripheral blood from adult donors, and the CCHMC Translational Research Trials Office for providing the regulatory and administrative support for studies with human cells. This research was supported by NIAID (R01AI087830 and R01AI100934) (S.S.W.) and NHLBI (R01HL103745) (A.F.S.). S.S.W. holds an Investigator in the Pathogenesis of Infectious Disease award from the Burroughs Wellcome Fund.

Author information


  1. Division of Infectious Diseases and Perinatal Institute, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA

    • Shokrollah Elahi
    • , James M. Ertelt
    • , Jeremy M. Kinder
    • , Tony T. Jiang
    • , Xuzhe Zhang
    • , Lijun Xin
    • , Vandana Chaturvedi
    • , Joseph E. Qualls
    •  & Sing Sing Way
  2. Center for Fetal Cellular and Molecular Therapy, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA

    • Beverly S. Strong
    •  & Aimen F. Shaaban
  3. Division of Gastroenterology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA

    • Kris A. Steinbrecher
  4. Division of Hematology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA

    • Theodosia A. Kalfa


  1. Search for Shokrollah Elahi in:

  2. Search for James M. Ertelt in:

  3. Search for Jeremy M. Kinder in:

  4. Search for Tony T. Jiang in:

  5. Search for Xuzhe Zhang in:

  6. Search for Lijun Xin in:

  7. Search for Vandana Chaturvedi in:

  8. Search for Beverly S. Strong in:

  9. Search for Joseph E. Qualls in:

  10. Search for Kris A. Steinbrecher in:

  11. Search for Theodosia A. Kalfa in:

  12. Search for Aimen F. Shaaban in:

  13. Search for Sing Sing Way in:


All authors performed or participated in the design of the experiments. S.E. and S.S.W. wrote the paper with editorial input from all authors.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Sing Sing Way.

Extended data

About this article

Publication history







By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.