New Insight into an Old Concept: Role of Immature Erythroid Cells in Immune Pathogenesis of Neonatal Infection

Abstract

Newborns are exceedingly susceptible to infection. However, very little is known about what governs the immunological differences seen in early life that result in extreme vulnerability to infection, nor how this changes during infancy. Herein, I provide evidence that the reduced ability to mount a protective immune response to pathogens is not due to an inherent immaturity of neonatal immune cells but instead the functions of these immune cells are actively suppressed by CD71+ erythroid cells. Furthermore, the role of CD71+ erythroid cells in host defense against infection is examined. CD71+ erythroid cells are enriched in newborns and have distinctive immunosuppressive properties that leave them vulnerable to infection. Moreover, immature erythroid cells possess exclusive immunomodulatory properties and may play a role in immune ontogeny. In addition to these distinct features, CD71+ erythroid cells impact digestive health by preventing excessive inflammation following the sudden transition from a sterile in utero setting to excessive colonization with commensals in the external environment. Ongoing research in identifying the beneficial and/or detrimental effects of immature erythrocytes on immune responses may serve to enhance protective newborn immune responses to infection and enable better vaccination strategies for the young to be designed.

Early life vaccination: Generation of adult-quality memory CD8+ T cells in infant mice using non-replicating adenoviral vectors

“…Taken together, these findings contradict the widely held notion that early-primed CD8+ T cells are functionally impaired and unable to produce multiple cytokines at the same levels as adults52. Indeed, our results support the idea that there are no intrinsic defects in the CD8+ T cells early in life, but rather that their activation is strictly regulated by the stimulating microenvironment53, and can be successfully triggered under the appropriate circumstances (see also ref. 54).…”

Umbilical cord CD71+ erythroid cells are reduced in neonates born to women in spontaneous preterm labor

“…The depletion of human CD71+ cells in cord blood samples unleashes the release of TNF-α and IL-6, as well as the activation of CD8+ T cells 11 . Therefore, umbilical cord CD71+ erythroid cells modulate fetal as well as neonatal immune responses 11, 19 . We found that umbilical cord CD71+ erythroid cells are more abundant in neonates born to women who delivered preterm without labor than in neonates born to women who delivered at term, regardless of the process of labor.…”

CD71+ erythroid cells from neonates born to women with preterm labor regulate cytokine and cellular responses

“…Nucleated erythroid cells express the general erythrocyte marker glycophorin A (or CD235a) [19, 21–23] as well as the transferrin receptor CD71, an antigen that is lost upon conversion to mature erythrocytes [24]. Previous studies indicated that CD71+ erythroid cells are partially responsible for immunosuppression of the neonatal immune system [21], and that a reduction in the number and/or functionality of these cells is observed in preterm newborns [25]. A follow-up study claimed, however, that these reticulocytes have a limited role in reducing inflammation driven by microbial colonization [26].…”

“…24 Previous studies indicated that CD71+ erythroid cells are partially responsible for immunosuppression of the neonatal immune system, 21 and that a reduction in the number and/or functionality of these cells is observed in preterm newborns. 25 A follow-up study claimed, however, that these reticulocytes have a limited role in reducing inflammation driven by microbial colonization. 26 Recently, we demonstrated that the number and frequency of CD71+ erythroid cells from neonates born to women who underwent spontaneous preterm labor (PTL) are similar to term neonates, but lower than those born to women who delivered preterm in the absence of labor.…”