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Malaghan Institute of Medical Research, Wellington School of Medicine, Wellington, New Zealand; and
Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543
The CD28 costimulatory pathway is critical to T cell activation.
Blockade of the interaction of CD28 with its ligands CD80 and CD86
using CTLA4-Ig has been proposed as a therapy for a number of
immune-based disorders. We have used a murine model of influenza virus
infection to study the role of CD28-dependent costimulation in the
development of antiviral immune responses. In vivo treatment with
CTLA4-Ig to block the interaction of CD28 with CD80 and CD86 reduced
virus-specific cytotoxicity and IFN-
production by bronchoalveolar
lavage fluid CD8+ T lymphocytes in vitro. It also resulted
in decreased numbers of virus-specific CD8+ T lymphocytes
in the bronchoalveolar lavage fluid, lung, and spleen and lowered
virus-specific Ab titers. Mice treated with CTLA4-Ig were able to
control and clear the virus infection, but this was delayed compared
with controls. Treatment with Y100F-Ig, a mutant form of CTLA4-Ig which
selectively binds to CD80 and blocks the CD28-CD80 interaction leaving
CD28-CD86 binding intact, did not affect Ab production, spleen
cytotoxic precursors, or clearance of virus. However, Y100F-Ig
treatment had a clear effect on lung effector cell function. Secretion
of IFN- by bronchoalveolar lavage fluid CD8+ T
lymphocytes in vitro was decreased, and the number of virus-specific
CD8+ T lymphocytes in the bronchoalveolar lavage fluid and
lungs of infected mice was reduced. These results indicate that
CD28-dependent costimulation is important in the antiviral immune
response to an influenza virus infection. The individual CD28 ligand,
CD80, is important for some lung immune responses and cannot always be
compensated for by CD86.
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