title: The fate of donor T-cell receptor transgenic T cells with known host antigen specificity in a graft-versus-host disease model.
abstract: BACKGROUND
  The expansion of transgenic donor CD8+ T-cells with known allospecificity against a host MHC class I alloantigen was examined in a murine graft-versus-host disease (GVHD) model.
  
  
  METHODS
  Lethally irradiated, Ld+ BALB/c mice received bone marrow cells and spleen cells from anti-Ld 2C T-cell receptor (TCR)-transgenic B6 mice, alone or with normal B6 spleen cells. Transgenic TCR-bearing T-cell expansion, apoptosis, and function were monitored at various time points and were correlated with clinical outcome.
  
  
  RESULTS
  Fifteen-fold clonal expansion of 2C CD8 cells occurred by day 4 after bone marrow transplantation. Between days 4 and 7, increasing proportions of 2C CD8 cells underwent apoptotic cell death, coincident with a 7-15-fold decline in their numbers. CD8 and TCR expression were down-regulated on 2C CD8 cells by day +4 after bone marrow transplantation, and they were anergic to TCR-mediated stimulation. Clinically, the BALB/c recipients of 2C spleen cells exhibited only minimal chronic GVHD. In contrast, lethally irradiated BALB/c mice receiving similar numbers of non-transgenic B6 bone marrow cells and spleen cells exhibited severe GVHD (median survival time: 28 days). The addition of a small number of 2C spleen cells to the inoculum accelerated GVHD mortality, and 2C CD8 cells showed a similar time course of expansion and decline to that observed in recipients of larger numbers of 2C cells alone.
  
  
  CONCLUSIONS
  Initial clonal expansion, down-regulation of CD8 and TCR, anergy, and later deletion of graft-versus-host-reactive CD8 cells via apoptosis occurs in lethally irradiated recipients. Expansion of a single CD8 clone produces much less severe GVHD than that induced by a polyclonal, mixed CD4 plus CD8 response. These results have implications for GVHD pathogenesis and its sometimes self-limited nature.
authors.affiliation: Transplantation Biology Research Center/Surgical Service, and Department of Pathology, Massachusetts General Hospital/Harvard Medical School, Boston 02129, USA.
authors.forename: B
authors.initials: B
authors.lastname: Dey
authors.forename: Y G
authors.initials: YG
authors.lastname: Yang
authors.forename: F
authors.initials: F
authors.lastname: Preffer
authors.forename: A
authors.initials: A
authors.lastname: Shimizu
authors.forename: K
authors.initials: K
authors.lastname: Swenson
authors.forename: D
authors.initials: D
authors.lastname: Dombkowski
authors.forename: M
authors.initials: M
authors.lastname: Sykes
mesh_terms: D000208:Acute Disease; D000818:Animals; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000528:radiation effects; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000502:physiology / Q000528:radiation effects; D002999:Clone Cells; D004195:Disease Models, Animal; D015536:Down-Regulation; D000939:Epitopes; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology / Q000473:pathology*; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000276:immunology* / Q000502:physiology; D013154:Spleen / Q000166:cytology / Q000528:radiation effects; D013601:T-Lymphocytes / Q000166:cytology / Q000528:radiation effects; D014916:Whole-Body Irradiation
chemical_list: D000939:Epitopes; D011948:Receptors, Antigen, T-Cell