The fate of donor T-cell receptor transgenic T cells with known host antigen specificity in a graft-versus-host disease model.
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.
Dey
B
B
Transplantation Biology Research Center/Surgical Service, and Department of Pathology, Massachusetts General Hospital/Harvard Medical School, Boston 02129, USA.
Yang
Y G
YG
Preffer
F
F
Shimizu
A
A
Swenson
K
K
Dombkowski
D
D
Sykes
M
M
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
D000939:Epitopes; D011948:Receptors, Antigen, T-Cell