CD36^himonocytes play immunoregulatory roles in human umbilical cord blood

Abstract

The fetal and neonatal immune systems are uniquely poised to generate tolerance to self, maternal, and environmental antigens encountered in the womb and shortly after birth. The tolerogenic nature of fetal and neonatal immunity is a rising health concern with the spread of vertically transmitted viruses, such as the Zika virus. A variety of mechanisms contribute to fetal and neonatal tolerance, including a propensity to generate Foxp3+ regulatory T cells (Tregs). Here, we demonstrate that a subset of CD14+ monocytes expressing the scavenger molecule, CD36, is able to generate CD4+ and CD8+ T cells that express Foxp3 from umbilical cord blood (UCB). Monocyte-induced Foxp3+ T cells have potent suppressive functions on T cell proliferation and maintain Foxp3 expression over six weeks in vitro. Importantly, UCB-derived Foxp3+ T cells are distinguishable from adult peripheral blood (APB) CD4+CD25+ Tregs by surface antigen expression. While UCB-derived Foxp3+ T cells express prototypic Treg-associated surface antigens, such as CD25 and glucocorticoid-induced tumor necrosis factor-related receptor (GITR), only UCB-derived Foxp3+ T cells express CD26. In addition, most UCB-derived CD8+Foxp3+ T cells express CD31. Mechanistically, both APB and UCB-derived monocytes support the development of Foxp3+ T cells from naïve T cells, but APB naïve T cells are less efficient in expressing Foxp3 than UCB naïve T cells. These data suggest that antigen presentation by CD36hi monocytes in the fetus leads to the development of a group of T cells that share some but not all phenotypes of adult thymus-derived Tregs.