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Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, TX 75390
Rapamycin (RAP), tacrolimus (FK506), cyclosporin A, and
glucocorticoids represent modern and classic immunosuppressive agents
being used clinically. Although these agents have distinct molecular
mechanisms of action and exhibit different immunoregulatory profiles,
their direct influences on Ag presentation processes remain relatively
unknown. Here we report quantitative and qualitative differences among
the above four immunosuppressants in their impact on Ag-specific,
bidirectional interaction between dendritic cells (DC) and
CD4+ T cells. In the presence of relevant Ag, bone
marrow-derived DC delivered activation signals to CD4+ T
cells isolated from the DO11.10 TCR transgenic mice, leading to clonal
expansion; secretion of IFN-
, IL-2, and IL-4; and surface expression
of CD69. Conversely, DO11.10 T cells delivered maturation signals to
DC, leading to IL-6 and IL-12 production and CD40 up-regulation. FK506
(10-10–10-8 M) and cyclosporin A
(10-9–10-7 M) each blocked efficiently and
uniformly all the changes resulting from intercellular signaling in
both DC
T cell and T cellDC directions. Dexamethasone
(10-9–10-6 M) suppressed all changes, except
for CD69 up-regulation, rather incompletely. Remarkably, RAP
(10-10–10-8 M) efficiently inhibited
DC-induced T cell proliferation and T cell-mediated CD40 up-regulation
by DC without abrogating other changes. Interestingly, T
cell-independent DC maturation triggered by LPS stimulation was
inhibited by dexamethasone, but not by other agents. Our results
demonstrate contrasting pharmacological effects of RAP vs calcineurin
inhibitors on Ag presentation, thus forming a conceptual framework for
rationale-based selection (and combination) of immunosuppressive agents
for clinical application.
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