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Blood, 15 March 2002, Vol. 99, No. 6, pp. 2146-2153
IMMUNOBIOLOGY
Negative effect of CTLA-4 on induction of T-cell immunity in vivo
to B7-1+, but not B7-2+, murine myelogenous
leukemia
James L. LaBelle,
Carrie A. Hanke,
Bruce R. Blazar, and
Robert L. Truitt
From the Department of Microbiology and Molecular
Genetics and the Department of Pediatrics, Medical College of
Wisconsin, Milwaukee; and the Cancer Center, Division of Bone Marrow
Transplantation, University of Minnesota, Minneapolis.
B7 molecules provide important costimulatory signals to T cells,
and B7 genes have been introduced into B7-negative tumor cells to
enhance their immunogenicity. However, the role of B7 molecules in
inducing tumor immunity is controversial because of conflicting results
and reports of differential signaling through the B7 molecules and
their ligands CD28 and CTLA-4. In this study, we compared the effect of
B7-1 (CD80) and B7-2 (CD86) on the induction of T-cell immunity to
C1498, a murine myelogenous leukemia. When cultured with exogenous
cytokines in vitro, C1498/B7-1 and C1498/B7-2 induced syngeneic
CD8+ T cells to kill parental C1498. In vivo, C1498/B7-1
grew progressively after subcutaneous injection, whereas C1498/B7-2
completely regressed after transient growth in naive mice. Spontaneous
rejection of C1498/B7-2 resulted in immunity to challenge doses of
C1498 and C1498/B7-1. Antibody-depletion studies in vivo showed that
CD8+ T cells rejected C1498/B7-2, whereas only natural
killer cells affected the growth of C1498/B7-1. Two approaches were
used to determine whether preferential interaction of B7-1 with CTLA-4 contributed to the failure of C1498/B7-1 to activate CD8+ T
cells in vivo. First, CTLA-4 specific monoclonal antibody was used to
block B7-1-CTLA-4 interaction. Second, CTLA-4 deletional mutant
( /) bone marrow chimeras were used as tumor hosts. In both systems,
there was a significant increase in the rate of rejection of C1498/B7-1
tumors. Resistance to C1498/B7-1 in CTLA-4 / hosts was
mediated by CD8+ T cells. Blocking or deletion of CTLA-4
did not affect the growth of parental C1498, indicating that B7-1 was
important for the induction of CD8+ T-cell immunity in the
absence of CTLA-4.
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