Donor deficiency of decay-accelerating factor accelerates murine T cell-mediated cardiac allograft rejection

J Immunol. 2008 Oct 1;181(7):4580-9. doi: 10.4049/jimmunol.181.7.4580.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD55 Antigens / biosynthesis
  • CD55 Antigens / genetics*
  • CD55 Antigens / physiology
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • Cells, Cultured
  • Complement Activation / genetics
  • Complement Activation / immunology
  • Cytotoxicity, Immunologic / genetics
  • Graft Rejection / genetics
  • Graft Rejection / immunology*
  • Graft Rejection / metabolism
  • Graft Rejection / pathology
  • Heart Transplantation / immunology*
  • Heart Transplantation / pathology
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, SCID
  • Mice, Transgenic
  • Pilot Projects
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism

Substances

  • CD55 Antigens
  • decay-accelerating factor 1, mouse