Donor deficiency of decay-accelerating factor accelerates murine T cell-mediated cardiac allograft rejection.
Decay-accelerating factor (DAF) is a cell surface regulator that accelerates the dissociation of C3/C5 convertases and thereby prevents the amplification of complement activation on self cells. In the context of transplantation, DAF has been thought to primarily regulate antibody-mediated allograft injury, which is in part serum complement-dependent. Based on our previously delineated link between DAF and CD4 T cell responses, we evaluated the effects of donor Daf1 (the murine homolog of human DAF) deficiency on CD8 T cell-mediated cardiac allograft rejection. MHC-disparate Daf1(-/-) allografts were rejected with accelerated kinetics compared with wild-type grafts. The accelerated rejection predominantly tracked with DAF's absence on bone marrow-derived cells in the graft and required allograft production of C3. Transplantation of Daf1(-/-) hearts into wild-type allogeneic hosts augmented the strength of the anti-donor (direct pathway) T cell response, in part through complement-dependent proliferative and pro-survival effects on alloreactive CD8 T cells. The accelerated allograft rejection of Daf1(-/-) hearts occurred in recipients lacking anti-donor Abs. The results reveal that donor DAF expression, by controlling local complement activation on interacting T cell APC partners, regulates the strength of the direct alloreactive CD8(+) T cell response. The findings provide new insights into links between innate and adaptive immunity that could be exploited to limit T cell-mediated injury to an allograft following transplantation.
Pavlov
Vasile
V
Department of Medicine, Transplant Institute and Immunology Institute, Mount. Sinai School of Medicine, New York, NY 10029, USA.
Raedler
Hugo
H
Yuan
Shuguang
S
Leisman
Staci
S
Kwan
Wing-Hong
WH
Lalli
Peter N
PN
Medof
M Edward
ME
Heeger
Peter S
PS
D000818:Animals; D018958:CD55 Antigens / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D003167:Complement Activation / Q000235:genetics / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016027:Heart Transplantation / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D008822:Mice, Transgenic; D010865:Pilot Projects; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
D018958:CD55 Antigens; C521184:decay-accelerating factor 1, mouse
Transplantation. 1999 Oct 15;68(7):1029-36
10532546
Immunity. 2008 Mar;28(3):425-35
18328742
Nat Med. 2002 Jun;8(6):582-7
12042808
J Immunol. 2008 May 1;180(9):5882-9
18424707
Blood. 2008 Sep 1;112(5):1759-66
18567839
J Immunol. 2003 Jan 15;170(2):788-94
12517942
J Immunol. 2004 Jan 1;172(1):240-7
14688331
Nat Med. 2004 Jan;10(1):87-92
14647496
J Immunol. 2004 Mar 15;172(6):3869-75
15004194
Am J Pathol. 2004 Apr;164(4):1407-15
15039228
J Immunol. 2004 May 1;172(9):5456-66
15100287
Transplantation. 2004 Sep 27;78(6):930-3
15385816
J Exp Med. 1984 Nov 1;160(5):1558-78
6238120
Biochemistry. 1986 Nov 4;25(22):6740-7
2432921
Ann N Y Acad Sci. 1988;532:76-85
2972246
J Immunol. 1998 Nov 15;161(10):5236-44
9820495
J Immunol. 1999 Jan 1;162(1):352-8
9886406
J Exp Med. 2005 Feb 21;201(4):567-77
15710649
Transplantation. 2005 May 15;79(9):1121-7
15880054
Nat Immunol. 2002 Sep;3(9):844-51
12172545
J Exp Med. 2005 May 16;201(10):1523-30
15883171
J Immunol. 2006 Jan 15;176(2):770-7
16393960
Transplantation. 2006 Jan 15;81(1):95-100
16421483
FASEB J. 2006 Feb;20(2):217-26
16449793
Blood. 2006 Mar 15;107(6):2461-9
16304047
J Immunol. 2006 Mar 15;176(6):3330-41
16517700
J Am Soc Nephrol. 2006 Apr;17(4):1102-11
16510763
J Leukoc Biol. 2007 Jan;81(1):212-20
16997854
J Immunol. 2007 Sep 1;179(5):3178-86
17709533
J Immunol. 2007 Oct 1;179(7):4451-63
17878341
J Immunol. 2007 Nov 1;179(9):5793-802
17947652
Immunology. 2001 Oct;104(2):215-25
11683962