Mechanism for cotolerance in nonlethally conditioned mixed chimeras: negative selection of the Vbeta T-cell receptor repertoire by both host and donor bone marrow-derived cells.
Bone marrow (BM) chimeras prepared by complete recipient ablation (A-->B) exhibit donor-specific tolerance, yet survival is often limited by graft-versus-host disease (GVHD). Negative selection of potentially donor-reactive T cells, as assessed by relative T-cell receptor (TCR)-Vbeta expression, is dependent on donor BM-derived deleting ligands. Mixed chimerism and tolerance for both donor and host antigens can be achieved using partial recipient myeloablation with 500 cGy total-body irradiation (TBI) before transplantation followed by cyclophosphamide (CyP) on day +2. To examine the influence of residual host elements on negative selection, the peripheral TCR-Vbeta repertoire was analyzed in partially ablated C57BL/10SnJ (B10) recipients reconstituted with BM from major histocompatibility complex (MHC)-disparate B10.BR/SgSnJ or MHC, Hh-1 and Mls-disparate BALB/cByJ donors, which delete Vbeta5+ and 11+ or Vbeta3+, 5+, and 11+ TCR subsets, respectively. As in myeloblated recipients, donor-reactive subfamilies were deleted in B10.BR-->B10 and BALB/c-->B10 chimeras, suggesting that donor I-E and minor lymphocyte-stimulating (Mls) antigens contribute to the deleting ligands in the nonmyeloablated host. In striking contrast to completely ablated B10-->B10.BR chimeras, partially ablated recipients showed intramedullary I-E expression in the thymus and deleted host-reactive Vbeta5+ and Vbeta11+ subfamilies. These data demonstrate that efficient clonal deletion occurs after partial myeloablation and that both donor and host ligands contribute to TCR repertoire selection.
Colson
Y L
YL
Department of Surgery, Division of Cellular Therapeutics, University of Pittsburgh, PA 15261, USA.
Lange
J
J
Fowler
K
K
Ildstad
S T
ST
D000818:Animals; D016465:Bone Marrow Purging; D017637:Clonal Deletion; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics*; D018183:Transplantation Chimera / Q000235:genetics*; D019172:Transplantation Conditioning
D016693:Receptors, Antigen, T-Cell, alpha-beta