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*
Laboratory of Experimental Immunology, Departments of
Pathology and
Gastroenterology, and
Laboratory of Experimental Hematology, University Hospital Gasthuisberg, Leuven, Belgium;
¶
Laboratory of Immunobiology, Rega Institute, University of Leuven, Leuven, Belgium;
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Tanox Pharma, Amersterdam, The Netherlands; and
#
Institute of Infectious Disease and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
CD28-B7 interaction plays a critical costimulatory role
in inducing T cell activation, while CTLA-4-B7 interaction
provides a negative signal that is essential in immune homeostasis.
Transfer of
CD45RBhighCD4+ T cells
from syngeneic mice induces transmural colon inflammation in SCID
recipients. This adoptive transfer model was used to investigate the
contribution of B7-CD28/CTLA-4 interactions to the control
of intestinal inflammation.
CD45RBhighCD4+ cells
from CD28-/- mice failed to induce mucosal
inflammation in SCID recipients. Administration of anti-B7.1 (but
not anti-B7.2) after transfer of wild-type
CD45RBhighCD4+ cells
also prevented wasting disease with colitis, abrogated leukocyte
infiltration, and reduced production of proinflammatory cytokines IL-2
and IFN-
by lamina propria CD4+ cells. In
contrast, anti-CTLA-4 treatment led to deterioration of disease, to
more severe inflammation, and to enhanced production of proinflammatory
cytokines. Of note,
CD25+CD4+ cells from
CD28-/- mice similar to those from the
wild-type mice were efficient to prevent intestinal mucosal
inflammation induced by the wild-type
CD45RBhigh cells. The inhibitory functions of
these regulatory T cells were effectively blocked by anti-CTLA-4.
These data show that the B7-CD28 costimulatory pathway is required for
induction of effector T cells and for intestinal mucosal inflammation,
while the regulatory T cells function in a CD28-independent way. CTLA-4
signaling plays a key role in maintaining mucosal lymphocyte tolerance,
most likely by activating the regulatory T
cells.
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