Aberrant regulation of superantigen responses during T-cell reconstitution and graft-versus-host disease in immunodeficient mice.
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.
Division of Molecular and Cellular Biology, Research Institute S-116A, Sunnybrook and Women's College Health Sciences Center, 2075 Bayview Avenue, Toronto, Ontario, Canada M4N 3M5. spanerd@srcl.sunnybrook.utoronto.ca
David
D
Spaner
Xiaofang
X
Sheng-Tanner
Andre C
AC
Schuh
D019264:Adoptive Transfer / Q000379:methods; D000818:Animals; D002470:Cell Survival; D004195:Disease Models, Animal; D006085:Graft Survival / Q000276:immunology; D006086:Graft vs Host Disease / Q000276:immunology*; D019891:Leukopoiesis / Q000276:immunology; D018655:Lymphocyte Count; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D018089:Superantigens / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000637:transplantation; D014185:Transplantation, Isogeneic / Q000473:pathology
D018089:Superantigens