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International Immunology, Vol. 11, No. 10, 1601-1614, October 1999
© 1999 Japanese Society for Immunology

Long-term persistence of IL-2-unresponsive allogeneic T cells in sublethally irradiated SCID mice

David Spaner1,2, Xiaofang Sheng-Tanner1, Kaliannan Raju2, Brian Rabinovich2, Hans Messner2 and Richard G. Miller2

1 Division of Cancer Biology Research, Sunnybrook Health Science Centre, Toronto, Ontario M4N 3MS, Canada
2 Department of Medical Biophysics, University of Toronto, and Ontario Cancer Institute, Toronto, Ontario M56 2M9, Canada

Correspondence to: D. Spaner, Division of Cancer Biology Research, Sunnybrook Health Science Centre, Research Building, S-Wing, Rm S-218, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada

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 106 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.

Keywords: graft versus host disease, immunosenescence, in vivoanimal model, superantigens, tolerance/suppression

Transmitting editor: R. H. Schwartz


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D. Spaner, X. Sheng-Tanner, and A. C. Schuh
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