CD71+ Erythroid Suppressor Cells Promote Fetomaternal Tolerance through Arginase-2 and PDL-1

J Immunol. 2018 Jun 15;200(12):4044-4058. doi: 10.4049/jimmunol.1800113. Epub 2018 May 7.

Abstract

Survival of the allogeneic pregnancy depends on the maintenance of immune tolerance to paternal alloantigens at the fetomaternal interface. Multiple localized mechanisms contribute to the fetal evasion from the mother's immune rejection as the fetus is exposed to a wide range of stimulatory substances such as maternal alloantigens, microbes and amniotic fluids. In this article, we demonstrate that CD71+ erythroid cells are expanded at the fetomaternal interface and in the periphery during pregnancy in both humans and mice. These cells exhibit immunosuppressive properties, and their abundance is associated with a Th2 skewed immune response, as their depletion results in a proinflammatory immune response at the fetomaternal interface. In addition to their function in suppressing proinflammatory responses in vitro, maternal CD71+ erythroid cells inhibit an aggressive allogeneic response directed against the fetus such as reduction in TNF-α and IFN-γ production through arginase-2 activity and PD-1/programmed death ligand-1 (PDL-1) interactions. Their depletion leads to the failure of gestation due to the immunological rejection of the fetus. Similarly, fetal liver CD71+ erythroid cells exhibit immunosuppressive activity. Therefore, immunosuppression mediated by CD71+ erythroid cells on both sides (mother/fetus) is crucial for fetomaternal tolerance. Thus, our results reveal a previously unappreciated role for CD71+ erythroid cells in pregnancy and indicate that these cells mediate homeostatic immunosuppressive/immunoregulatory responses during pregnancy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / immunology*
  • Arginase / immunology*
  • B7-H1 Antigen / immunology*
  • Erythroid Cells / immunology*
  • Female
  • Humans
  • Immune Tolerance / immunology*
  • Immunosuppression Therapy / methods
  • Interferon-gamma / immunology
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Pregnancy
  • Receptors, Transferrin / immunology*
  • Th2 Cells / immunology
  • Tumor Necrosis Factor-alpha / immunology

Substances

  • Antigens, CD
  • B7-H1 Antigen
  • CD71 antigen
  • Cd274 protein, mouse
  • Receptors, Transferrin
  • Tumor Necrosis Factor-alpha
  • Interferon-gamma
  • Arg2 protein, mouse
  • Arginase

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