Bim regulates alloimmune-mediated vascular injury through effects on T-cell activation and death.
OBJECTIVE
Bim is a proapoptotic Bcl-2 protein known to downregulate immune responses and to also be required for antigen-induced T-cell activation. However, it is not known how the effect of Bim on these offsetting processes determines the outcome of allogeneic immune responses. We have defined the role of Bim in regulating alloantigen-driven T-cell responses in a model of vascular rejection.


RESULTS
Bim was required for proliferation of CD4 and CD8 T cells, and for interleukin-2 production, in T cells stimulated with alloantigen in vitro. Moreover, a partial reduction in Bim expression was sufficient to attenuate T-cell activation, whereas a complete elimination of Bim was required to prevent CD4 T-cell death in response to cytokine withdrawl. When alloimmune-mediated vascular rejection was examined using an aortic interposition model, there was significantly less intimal thickening in Bim(+/-), but not Bim(-/-), graft recipients. T-cell proliferation in response to allograft arteries was significantly reduced in both Bim(+/-) and Bim(-/-) mice, but cell death was attenuated only in Bim(-/-) animals.


CONCLUSIONS
Bim controls both T-cell activation and death in response to alloantigen stimulation. These processes act cooperatively to determine the outcome of immune responses in allograft arteries.
From the Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada (A.v.R., W.E., Y.P.S., G.E.M., J.C.C.); and Terry Fox Laboratory, BC Cancer Agency, Vancouver, British Columbia, Canada (M.M., R.B.).
Anna
A
von Rossum
From the Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada (A.v.R., W.E., Y.P.S., G.E.M., J.C.C.); and Terry Fox Laboratory, BC Cancer Agency, Vancouver, British Columbia, Canada (M.M., R.B.).
Winnie
W
Enns
From the Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada (A.v.R., W.E., Y.P.S., G.E.M., J.C.C.); and Terry Fox Laboratory, BC Cancer Agency, Vancouver, British Columbia, Canada (M.M., R.B.).
Yu P
YP
Shi
From the Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada (A.v.R., W.E., Y.P.S., G.E.M., J.C.C.); and Terry Fox Laboratory, BC Cancer Agency, Vancouver, British Columbia, Canada (M.M., R.B.).
Grace E
GE
MacEwan
From the Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada (A.v.R., W.E., Y.P.S., G.E.M., J.C.C.); and Terry Fox Laboratory, BC Cancer Agency, Vancouver, British Columbia, Canada (M.M., R.B.).
Mehrnoush
M
Malekesmaeli
From the Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada (A.v.R., W.E., Y.P.S., G.E.M., J.C.C.); and Terry Fox Laboratory, BC Cancer Agency, Vancouver, British Columbia, Canada (M.M., R.B.).
Ryan
R
Brinkman
From the Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada (A.v.R., W.E., Y.P.S., G.E.M., J.C.C.); and Terry Fox Laboratory, BC Cancer Agency, Vancouver, British Columbia, Canada (M.M., R.B.). jonathan.choy@sfu.ca.
Jonathan C
JC
Choy
D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000502:physiology*; D000072224:Bcl-2-Like Protein 11; D016207:Cytokines / Q000502:physiology; D005260:Female; D006084:Graft Rejection / Q000209:etiology; D007519:Isoantigens / Q000276:immunology*; D008213:Lymphocyte Activation; D008297:Male; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology*; D014184:Transplantation, Homologous; D014652:Vascular Diseases / Q000209:etiology*
D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D016207:Cytokines; D007519:Isoantigens; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins
Bim protein; T-cell; transplantation; vascular system injuries