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Blood, 15 September 2002, Vol. 100, No. 6, pp. 2216-2224
TRANSPLANTATION
Aberrant regulation of superantigen responses during T-cell
reconstitution and graft-versus-host disease in
immunodeficient mice
David Spaner,
Xiaofang Sheng-Tanner, and
Andre C. Schuh
From the Division of Molecular and Cellular Biology,
Research Institute, Sunnybrook and Women's College Health Sciences
Center, Toronto, Ontario, Canada; and the Departments of Medicine, and
Medical Biophysics, and the Institute of Medical Sciences, University
of Toronto, Ontario, Canada
Acute graft-versus-host disease (GVHD) after allogeneic stem cell
transplantation is associated with impaired deletion and anergy of
host-reactive T cells. To elucidate the immunoregulatory events that
may contribute to such dysregulated T-cell responses in GVHD, we
studied superantigen (SAg) responses after adoptive T-cell
transfer into severe combined immunodeficient (SCID) mice. SAg
responses are normally regulated by mechanisms involving deletion and
anergy, with SAg-reactive T cells typically being deleted rapidly in
vivo. In a SCID mouse model of GVHD, however, allogeneic host
SAg-reactive T cells were not deleted rapidly, but rather persisted in
increased numbers for several months. Moreover, depending on the timing
of SAg stimulation and the numbers of T cells transferred, dysregulation (impaired deletion and anergy) of SAg responses could be
demonstrated following the adoptive transfer of syngeneic T cells into
SCID mice as well. Transgenic T-cell receptor-bearing KJ1-26.1+ T cells were then used to determine the fate of
weakly reactive T cells after adoptive transfer and SAg stimulation.
When transferred alone, KJ1-26.1+ T cells demonstrated
impaired deletion and anergy. In the presence of more strongly
staphylococcal enterotoxin B (SEB)-reactive T cells, however,
KJ1-26.1+ T cells were regulated normally, in a manner that
could be prevented by inhibiting the effects of more strongly
SEB-reactive cells or by increasing the level of activation of the
KJ1-26.1+ T cells themselves. We suggest that the control
mechanisms that normally regulate strongly activated T cells in
immunocompetent animals are lost following adoptive transfer into
immunodeficient hosts, and that this impairment contributes to the
development of GVHD.
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