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Blood, Vol. 95 No. 10 (May 15), 2000:
pp. 3153-3161
Blockade of CD86 and CD40 induces alloantigen-specific
immunoregulatory T cells that remain anergic even after reversal of
hyporesponsiveness
Hans J. P. M. Koenen and
Irma Joosten
From the Department for Blood Transfusion and Transplantation
Immunology, University Medical Center, St Radboud, Nijmegen, The
Netherlands.
The generation of immunoregulatory T cells that block the
B7(CD86/CD80)-CD28 and/or CD40-CD154 costimulatory pathways has great
potential for the induction of long-term transplantation tolerance. In
a human polyclonal in vitro model, combined monoclonal antibody (mAb)
blocking of the costimulatory ligands CD40 and CD86 lead to
allospecific T-cell anergy that cannot be reversed by antigenic
rechallenge in the presence of IL-2. Although antigenic restimulation
with IL-2 restored the proliferative response, subsequent antigenic
restimulation of the restored anergic cells in a tertiary mixed
lymphocyte culture still resulted in nonresponsiveness. Importantly, these anergic T cells suppress the response of naive alloreactive T cells in an antigen-specific way via linked recognition. Suppression may partially depend on local IL-10 production, while transforming growth factor- (TGF-) did not play a role.
Irrespective of the monoclonal antibody combination used, blast
formation occurred in a subset of CD4+ cells. These cells
were characterized by a sustained CD45RA expression, an increased
T-cell receptor density, and a lower level of CD4 expression. A reduced
number of CD45RO+/CD8+ T cells was observed
whenever anti-CD86 was combined with anti-CD40, which was reflected by
an even more attenuated cytotoxic T-cell function. This indicates the
importance of CD40-CD154 in the generation of cytotoxic T cells in this
transplantation model. We hypothesize that in our model, anergy is
induced in the CD4+ T-cell subset, whereby
CD8+ cytotoxic effector function is impaired by the lack
of both CD40-CD154 signaling and cytokine-mediated help. This
costimulatory ligand-directed mAb approach might well be used for the
ex vivo generation of antigen-specific immunoregulatory T cells
applicable in adoptive immunotherapy.
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