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.

Keywords: CD71 cells; digestive health; erythroid cells; innate immunity; microbiota; neonates.

Figure 1

Model depicting how CD71⁺ erythroid cells mediate immunomodulatory functions. CD71⁺ erythroid cells by secreting soluble immunosuppressive factors, depletion of arginine, and direct cell–cell contact manners inhibit CD4, CD8, B cell, macrophage (MQ), and dendritic cell (DC) responses. CD71⁺ erythroid cells could also skew a Th2 type immune response or expand regulatory T cells (Tregs), by the production of cytokines and influence on the cytokine milieu.

Figure 2

Model depicting differential factors influencing intestinal homeostasis in full term versus preterm newborns. High proportion of CD71⁺ erythroid cells in full term infants skews their immune response toward a Th2 phenotype which influences the bacterial composition to a diverse commensal colonization and subsequently a regulated intestinal immune response. Whereas, lower frequency of CD71⁺ erythroid cells in preterm infants results in a Th1 bias immune response, which favors colonization of the gut with more pathogenic bacteria, subsequently predisposes the preterm to necrotizing entrocolitis (NEC).

Figure 3

Proposed mechanisms of CD71⁺ erythroid cells-induced gut immune-regulation in full term versus preterm newborns. In full terms, enriched CD71⁺ erythroid cells generate a suppressed immune environment by regulatory and Th2 type cytokine in the intestine, which down-regulates TLR expression, maintains symbiosis and intestinal integrity. In contrast, lower and/or dysfunctional CD71⁺ erythroid cells in preterm disrupts normal immune homeostasis in the gut leading to a switch from a suppressed environment to a pro-inflammatory state, up-regulates TLR expression, dysbiosis, and pathological alterations associated with NEC.