Long-term persistence of IL-2-unresponsive allogeneic T cells in sublethally irradiated SCID mice.
Donor T cells that are activated by host alloantigens initiate graft versus host disease (GVHD) but their long-term fate is poorly understood. The behavior of alloreactive donor T cells was studied in sublethally irradiated SCID mice. Intravenous injection of 10(6) allogeneic lymphocytes caused a severe form of GVHD, characterized by host hematopoietic atrophy. Fifty-fold fewer donor cells did not induce disease and were not simply rejected by radioresistant host mechanisms. Instead, low numbers of allogeneic T cells expanded 20- to 50-fold and remained for >1 year without causing evidence of GVHD. Persistent non-cycling donor cells with an activated phenotype were mainly found in the spleen. Tolerance was inferred by the recovery of host hematopoiesis, despite the presence of donor allogeneic T cells, and the inability of long-term persisting donor T cells to mediate cellular cytotoxicity or proliferate in response to exogenous IL-2 or antigenic stimulation in vitro. The TCR density of long-term persisting donor T cells was down-regulated. These findings suggest that the development of GVHD depends on the magnitude of the initial anti-host response. Subsequently donor cells differentiate, over several months, into a senescent-like state. This behavior questions the rationale for current treatment approaches to GVHD and is of relevance to any clinical situation where chronic T cell activation takes place in the absence of thymic development.
Spaner
D
D
Division of Cancer Biology Research, Sunnybrook Health Science Centre, Toronto, Ontario M4N 3MS, Canada.
Sheng-Tanner
X
X
Raju
K
K
Rabinovich
B
B
Messner
H
H
Miller
R G
RG
D000818:Animals; D002460:Cell Line; D016922:Cellular Senescence; D004195:Disease Models, Animal; D005434:Flow Cytometry; D006086:Graft vs Host Disease / Q000276:immunology* / Q000473:pathology; D007111:Immunity, Cellular; D007371:Interferon-gamma / Q000032:analysis; D007376:Interleukin-2 / Q000494:pharmacology*; D015847:Interleukin-4 / Q000032:analysis; D008099:Liver / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D013154:Spleen / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000528:radiation effects / Q000637:transplantation; D013997:Time Factors; D014184:Transplantation, Homologous; D014916:Whole-Body Irradiation
D007376:Interleukin-2; D015847:Interleukin-4; D007371:Interferon-gamma