Prenatally Educated Friendly NK Cells Expand FOXP3+Tregs and Reduce Tc17 Cells Via Increased TGF-B1 and Decreased GM-CSF Production 4833

Abstract Description Prenatal foreign antigen exposure before immune competence results in lifelong antigen-specific tolerance. In our prenatal allotransplantation model, tolerant NK cells (engrafter friendly NK, fNK) suppressed type 1 and 17 allo-specific T cell responses via increased TGF-b1 production and Foxp3+CD4+Treg expansion. TGF-b1 also has different effects on the induction of Treg and Th17/Tc17 cells. Therefore, we hypothesized that engrafter fNK cells can suppress type 17 allo-specific T cell responses by changing the ratio of Tregs to Tc17. For this, we analyzed the cytokine profiles of fNK cells and examined the ratio of Tregs to Tc17 cells in vivo through gain and loss of function experiments. Both (Ly49AFG+) fNK cells and Thy1.2+T cells or Thy1.2+T cells alone were depleted and then naïve responder Thy1.1+ T cells and donor targets were adoptively transferred into host chimeras. We found that engrafter fNK produced higher LAP (TGF-b1) levels upon PI and ant-NK1.1 stimulation. Furthermore, the rejecter fNK cells exhibit a higher level of GM-CSF upon specific stimulation activation of the cognate receptor. The fNK cell-replete engrfters exhibited a higher ratio of Foxp3+CD4+Tregs to allo-specific RORgt+ CD8 T cells than the fNK cell-depleted. These studies conclude that prenatally educated fNK cells can exert regulatory effects on type 17 allo-specific T cell responses by increasing the ratio of Tregs to Tc17 cells via increasing TGF-b1 but decreasing GM-CSF. Funding Sources Supported by R01HL103745 and Lurie Children’s Hospital Research Foundation to A.F.S. Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)