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Receptors Are Critical for Acute CD4+ T Cell-Mediated Cardiac Allograft Rejection1
*
Division of Nephrology, Department of Medicine, and
Division of Cardiology, Department of Pediatrics, The Children’s Hospital,
Department of Pathology, Veterans Affairs Medical Center, and
Barbara Davis Center for Childhood Diabetes, Department of Medicine and Immunology, University of Colorado Health Sciences Center, Denver, CO 80262
Recent studies using mouse models demonstrate that CD4+
T cells are sufficient to mediate acute cardiac allograft rejection in
the absence of CD8+ T cells and B cells. However, the
mechanistic basis of CD4-mediated rejection is unclear. One potential
mechanism of CD4-mediated rejection is via elaboration of
proinflammatory cytokines such as IFN-
. To determine whether IFN-
is a critical cytokine in CD4-mediated acute cardiac allograft
rejection, we studied whether the expression of IFN- receptors on
the donor heart was required for CD4-mediated rejection. To investigate
this possibility, purified CD4+ T cells were transferred
into immune-deficient mice bearing heterotopic cardiac allografts from
IFN- receptor-deficient (GRKO) donors. While CD4+ T
cells triggered acute rejection of wild-type heart allografts, they
failed to trigger rejection of GRKO heart allografts. The impairment in
CD4-mediated rejection of GRKO hearts appeared to primarily involve the
efferent phase of the immune response. This conclusion was based on the
findings that GRKO stimulator cells provoked normal CD4 proliferation
in vitro and that intentional in vivo challenge of CD4 cells with
wild-type donor APC or the adoptive transfer of in vitro primed CD4 T
cells failed to provoke acute rejection of GRKO allografts. In
contrast, unseparated lymph node cells acutely rejected both GRKO and
wild-type hearts with similar time courses, illustrating the existence
of both IFN--dependent and IFN--independent mechanisms of acute
allograft rejection.
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