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Blood, 15 March 2002, Vol. 99, No. 6, pp. 2228-2234
TRANSPLANTATION
Differential effect of CD28 versus B7 blockade on direct pathway
of allorecognition and self-restricted responses
Fabienne Haspot,
Florence Villemain,
Geneviève Laflamme,
Flora Coulon,
Daniel Olive,
Jérôme Tiollier,
Jean-Paul Soulillou, and
Bernard Vanhove
From ITERT-INSERM U437, Nantes; INSERM U119, Marseille;
and Sangstat Europe, Lyon, France.
Immunosuppression with B7 antagonists might have 2 opposite
effects: reducing T-cell costimulation through CD28 but also preventing CTLA-4 from transmitting its negative regulatory signal. We therefore hypothesized that a selective blockade of CD28 might be qualitatively different from blocking B7. It was previously reported that CD28 modulation prolongs allograft survival in the rat and reverses induction of experimental autoimmune encephalomyelitis in mice. However, whether CD28 or B7 blockade results in similar
immunosuppression on alloimmune and self-restricted responses to
soluble antigens has not yet been investigated. Here, we addressed this
issue in vitro with antagonist anti-CD28 Fab fragments and in vivo
using the modulating anti-rat JJ319 monoclonal antibody. As in the
inhibition of B7 with CTLA4 immunoglobulin, anti-CD28 Fab fragments
inhibited allogenic T-cell proliferation in mixed cultures. In vivo
modulation of CD28 blocked the expansion of alloreactive T cells and
promoted their apoptosis. In contrast, selective blockade of CD28 did
not modify T-cell proliferative responses and antibody production to
soluble antigens, whereas blocking B7 with CTLA4 immunoglobulin did.
Our data show that blocking CD28, while leaving CTLA4-B7 interactions
undisturbed, inhibits alloreactive CD4+ T-cell expansion
but does not modify the response to nominal antigens presented in
the context of a self-major histocompatibility complex. That B7
engagement is needed for self-restricted responses whereas
engagement of CD28 is not essential adds to the suggestion that another
unidentified ligand of B7 might deliver a costimulatory signal in the
absence of CD28.
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