Resistance of Foxp3+ regulatory T cells to Nur77-induced apoptosis promotes allograft survival

Abstract

The NR4A nuclear receptor family member Nur77 (NR4A1) promotes thymocyte apoptosis during negative slection of autoreactive thymocytes, but may also function in mature extrathymic T cells. We studied effects of over-expression of Nur77 on the apoptosi of murine peripheral T cells, including thymic-derived Foxp3+ regulatory (Treg) cells. Overexpression of Nur77 in the T cell lineage decreased numbers of peripheral CD4 and CD8 T cells by -80% compared to wild-type (WT) mice. However, the proportions of Treg cells were markedly increased in the thymus (61% of CD4+Foxp3+ singly positive thymocytes vs. 8% in WT) and secondary lymphoid organs (40-50% of CD4+Foxp3+ T cells vs. 7-8% in WT) of Nur77 transgenic (Nur77Tg) mice, and immunoprecipitation studies showed Nur77 was associated with a recently identified HDAC7/Foxp3 transcriptional complex. Upon activation through the T cell receptor in vitro or in vivo, Nu77Tg T cells showed only marginally decreased proliferation but signficantly increased apoptosis. Fully allogeneic cardiac graft transplanted to. Nur77Tg mice survived long-term with well-preserved structur, and recipient splenocytes showed markedly enhanced apoptosis and greatly reduced anti-donor recall responses. Allografts in Nur77Tg recipients had significantly indeased expression of multiple Treg-associated genes, including Foxp1, Tip60 and HDAC9. Allograft rejection was restored by CD25 monoclonal antibody therapy, indicating that allograft acceptance was dependeent upon Treg function in Nur77Tg recipients. These data show that compared to conventional CD4 and CD8 T cells, Foxp3+ Tregs are relatively resistant to Nur77-mediated apoptosis, and that tipping the balance between the numbers of Tregs and responder T cells in the period post-transplantation can determine the allograft. Hence, induced expression of Nur77 might be a novel means to achieve long-term allograft survival. © 2008 Tao, Hancock.