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* Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104;
Bristol-Myers Squibb Pharmacology Research Institute, Princeton, NJ 08543; and
Amgen Inc., Thousand Oaks, CA 91320
Long-term resistance to Toxoplasma gondii is
dependent on the development of parasite-specific T cells that produce
IFN-
. CD28 is a costimulatory molecule important for optimal
activation of T cells, but CD28-/- mice are resistant to
T. gondii, demonstrating that CD28-independent
mechanisms regulate T cell responses during toxoplasmosis. The
identification of the B7-related protein 1/inducible costimulator
protein (ICOS) pathway and its ability to regulate the
production of IFN- suggested that this pathway may be involved in
the CD28-independent activation of T cells required for resistance to
T. gondii. In support of this hypothesis, infection of
wild-type or CD28-/- mice with T. gondii
resulted in the increased expression of ICOS by activated
CD4+ and CD8+ T cells. In addition, both
costimulatory pathways contributed to the in vitro production of
IFN- by parasite-specific T cells and when both pathways were
blocked, there was an additive effect that resulted in almost complete
inhibition of IFN- production. Although in vivo blockade of the ICOS
costimulatory pathway did not result in the early mortality of
wild-type mice infected with T. gondii, it did lead to
increased susceptibility of CD28-/- mice to T.
gondi associated with reduced serum levels of IFN-,
increased parasite burden, and increased mortality compared with the
control group. Together, these results identify a critical role for
ICOS in the protective Th1-type response required for resistance to
T. gondii and suggest that ICOS and CD28 are parallel
costimulatory pathways, either of which is sufficient to mediate
resistance to this intracellular pathogen.
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