Prenatal Rejecter NK Cells Enhance Allo-specific Th17/Tc17 Cell Responses via TGF-beta1, IL-6 and GM-CSF.

Abstract In utero hematopoietic cellular transplantation (IUHCT) has the potential to treat congenital benign cellular disease without chemotherapy or radiation. Prenatal tolerance is essential in this regard. Previous studies involving prenatally created chimeras have shown that immunologically tolerant NK cells (friendly, fNK) from engrafter mice suppress allo Tc1 responses, while intolerant NK cells (hostile, hNK) from rejecter mice enhance allo Tc1 responses. Given that Th17 cells are also involved in allograft rejection, we sought to determine if rejecter hNK cells induce/expand allo-specific Th17/Tc17 cells. We examined the helper potential of prenatally educated hNK cells in non-tolerant prenatal Balb/c --- > B6.Thy1.2 rejecter chimeras. Naïve Thy1.1+ responder T cells and allogenic target cells were adoptively transferred into rejecter or naïve hosts that had been depleted of endogenous T cells and fNK cells. We found increased Th17/Tc17 alloimmunity in the responder Thy1.1+T cell population in rejecters when compared to naïve hosts. Additionally, through ELISPOT, we confirmed increased IL-17A production by responder T cells when co-cultured with allo-specific hNK cells from rejecter mice. Hostile NK cells from rejecter mice produce higher levels of Th17 driving cytokines, TGF-beta 1, IL-6 and GM-CSF when compared to naïve hNK. From these results, we conclude that prenatal rejecter hNK cells have an enhanced helper effect on Th17/Tc17 alloimmunity in vivo and in vitro. These findings support an evolving paradigm that prenatally educated NK cell can regulate the balance between Th1/Th17 and Treg functions. Supported by NIH R01HL103745 Lurie Children’s Hospital Research Foundation (to A.F.S.)