Neonatal CD71+ Erythroid Cells Do Not Modify Murine Sepsis Mortality

Abstract

Sepsis is a major cause of neonatal mortality and morbidity worldwide. A recent report suggested murine neonatal host defense against infection could be compromised by immunosuppressive CD71+ erythroid splenocytes. We examined the impact of CD71+ erythroid splenocytes on murine neonatal mortality to endotoxin challenge or polymicrobial sepsis and characterized circulating CD71+ erythroid (CD235a+) cells in human neonates. Adoptive transfer or antibody-mediated reduction of neonatal CD71+ erythroid splenocytes did not alter murine neonatal survival to endotoxin challenge or polymicrobial sepsis challenge. Ex vivo immunosuppression of stimulated adult CD11b+ cells was not limited to neonatal splenocytes as it also occurred with adult and neonatal bone marrow. Animals treated with anti-CD71 antibody showed reduced splenic bacterial load following bacterial challenge compared to isotype-treated mice. However, adoptive transfer of enriched CD71+ erythroid splenocytes to CD71+-reduced animals did not reduce bacterial clearance. Human CD71+CD235a+ cells were common among cord blood mononuclear cells and were shown to be reticulocytes. In summary, a lack of effect on murine survival to polymicrobial sepsis following adoptive transfer or diminution of CD71+ erythroid splenocytes under these experimental conditions suggests the impact of these cells on neonatal infection risk and progression may be limited. An unanticipated immune priming effect of anti-CD71 antibody treatment was likely responsible for the reported enhanced bacterial clearance, rather than a reduction of immunosuppressive CD71+ erythroid splenocytes. In humans, the well-described rapid decrease in circulating reticulocytes after birth suggests they may have a limited role in reducing inflammation secondary to microbial colonization.

An Immunological Perspective on Neonatal Sepsis

“…These authors suggested that CD71+ nucleated red blood cells (nRBCs) actively suppress both innate and adaptive immune responses through the expression of arginase, which inhibits nitric oxide synthesis [72]. However, this conclusion was disputed by others whose data suggested that the heightened intestinal immune activation in mice treated with anti-CD71 to deplete the nRBCs was unaffected by replenishment of these cells [73]. Of note, significant cross-contamination can occur between nRBCs and other white blood cells types during cell purification for ex vivo immune studies [74].…”

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

“…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 are similar to term neonates, but lower than those born to women who delivered preterm in the absence of labor [27].…”

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

“…Neonatal CD71+ erythroid cells seem to participate in the colonization of commensal microorganisms, which occurs shortly after parturition 11 . However, this role is still controversial 12 since CD71 is highly expressed in the gut epithelium 13 . Therefore, the enhanced bacterial clearance that occurs upon anti-CD71 treatment may be the result of diminished intestinal barrier function (i.e.…”

“…Therefore, the enhanced bacterial clearance that occurs upon anti-CD71 treatment may be the result of diminished intestinal barrier function (i.e. immune priming by leaked microbiota) rather than the absence of CD71+ erythroid cells 12 .…”