DN-Treg cells induce long-term cardiac allograft survival in fully MHC mismatched recipients but do not eliminate T memory cells (145.13)

Abstract

Abstract Establishment of immune tolerance is a major goal in transplantation. Regulatory T (Treg) cells play an important role in the regulation of immune responses. Our previous studies have shown that TCRαβ+CD3+CD4-CD8-NK1.1- (double negative, DN) Treg cells suppress anti-donor T cell responses and prolong allograft survival in a single MHC-mismatched mouse model. In this study, we tested whether DN-Treg cells can induce long-term graft survival in the stringent BALB/c to C57BL/6 heart transplant model. Adoptive transfer of 107 DN-Treg cells in combination with rapamycin (RAPA) treatment (day 1- 9) induced long-term graft survival (101 vs. 39 days RAPA alone, p<0.01). DN-Treg treated recipients had few graft-infiltrating CD4+ and CD8+ T cells on day 40 compared to massive infiltration in RAPA treated controls. Memory T (Tm) cells (CD3+CD44+) were found to be resistant to DN-Treg cell-mediated suppression in vitro. The effect of DN-Treg on Tm in vivo was tested in B6-Rag1-/- mice. DN-Treg cells along with CD44+ Tm cells modestly prolonged BALB/c skin graft survival in contrast to DN-Treg with CD44- T cells (26 vs 43 days, P<0.001). In conclusion, DN-Treg cells combined with short term immunosuppression, can prolong allograft survival in the absence of tolerance. Furthermore, this may be related to the resistance of Tm cells to DN-Treg cell suppression, suggesting alternative strategies will be needed to control Tm cells and establish tolerance after transplantation.