Prenatally Educated Friendly NK Cells regulate Allo-specific T cell Responses through expansion of Foxp3+CD4+Treg Cells and suppression of Type 1 and 17 CD8+T cell responses.

Abstract

Abstract Prenatal alloantigen exposure during embryonic development permanently tolerizes the early gestational fetus and provides a tremendous advantage over transplantation after birth. However, the influence of prenatally educated NK cells on alloantigen-specific T cell immune responses is not well elucidated. In previous experiments, we found that prenatally-educated friendly NK (fNK) cells exert suppressive effects on allo-specific T cell responses in vitro. We hypothesized that prenatally-educated fNK cells exert regulatory effects on allo-specific T cells in vivo. To challenge this hypothesis, we examined the regulatory potential of prenatally educated fNK cells through gain and loss of function experiments in stable prenatal Balb/c --> B6.Thy1.2+ chimeras (engrafter mice). We depleted both (Ly49AFG+) fNK cells and Thy1.2+T cells or Thy1.2+T cells alone in host engrafter mice and then adoptively transferred naïve responder Thy1.1+ T cells along with donor-specific allogeneic or syngeneic target cells into the engrafter hosts. We found that the fNK cell-replete animals exhibited a higher frequency of foxp3+Tregs and a lower frequency of allospecific T-bet+ and RORγt+ CD8 T cells compared to the fNK cell-depleted controls. Furthermore, the neutralization of TGF-β1 decreased the fNK cell-induced expansion of Treg cells in vitro. From these studies, we conclude that prenatally educated fNK cells exert regulatory effects on allo-specific T-cell responses through the TGF-β1 mediated expansion of foxp3+Treg cells. Prenatal antigen experience drives the emergence of antigen-specific suppressors that regulate T cell responses. National Institutes of Health Grant R01HL103745 and Lurie Children’s Hospital Research Foundation (to A.F.S.)