Transplantation tolerance in NF-kappaB-impaired mice is not due to regulation but is prevented by transgenic expression of Bcl-xL.
NF-kappaB is a key regulator of transcription after TCR and costimulatory receptor ligation. To determine the role of T cell-intrinsic NF-kappaB activation in acute allograft rejection, we used IkappaBalphaDeltaN-Tg mice (H-2b) that express an inhibitor of NF-kappaB restricted to the T cell compartment. We have previously shown that these mice permanently accept fully allogeneic (H-2d) cardiac grafts and secondary donor skin grafts, and that splenocytes from these tolerant mice have reduced alloreactivity when restimulated in vitro. These results were compatible with either deletion or suppression of allospecific T cells as possible mechanisms of tolerance. The aim of this study was to investigate the mechanism of transplant tolerance in these mice. IkappaBalphaDeltaN-Tg mice did not have increased numbers or function of CD4+ CD25+ regulatory T cells either before or after cardiac transplantation. In addition, tolerance could not be transferred to fresh NF-kappaB-competent T cells and was not permissive for linked suppression to skin grafts sharing donor and third-party alloantigens, suggesting that dominant suppression is not the mechanism by which IkappaBalphaDeltaN-Tg mice achieve tolerance. In contrast, overexpression of the antiapoptotic protein Bcl-xL in T cells from IkappaBalphaDeltaN-Tg mice resulted in effective rejection of cardiac allografts and correlated with an increased frequency of splenocytes producing IFN-gamma in response to alloantigen. Together, these results suggest that the death of alloreactive T cells may be partly responsible for the transplantation tolerance observed in mice with defective T cell-intrinsic NF-kappaB activation.
Zhou
Ping
P
Department of Medicine, Section of Rheumatology, Committee on Immunology, University of Chicago, Chicago, IL 60637, USA.
Balin
Samuel J
SJ
Mashayekhi
Mona
M
Hwang
Kwang Woo
KW
Palucki
David A
DA
Alegre
Maria-Luisa
ML
D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D006084:Graft Rejection / Q000276:immunology; D006183:H-2 Antigens; D016027:Heart Transplantation / Q000276:immunology; D020672:I-kappa B Proteins / Q000235:genetics / Q000276:immunology; D007108:Immune Tolerance; D007371:Interferon-gamma / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000276:immunology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000276:immunology*; D016038:Skin Transplantation / Q000276:immunology; D014181:Transplantation Immunology; D051020:bcl-X Protein
C494812:Bcl2l1 protein, mouse; D006183:H-2 Antigens; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D000072000:NF-KappaB Inhibitor alpha; D007371:Interferon-gamma