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Department of Pharmacology, University of Bath, Bath, United Kingdom; and Bath Institute for Rheumatic Diseases, Bath, United Kingdom
Although the role of CD28 in T cell costimulation is firmly
established, the mechanisms by which it exerts its costimulatory
actions are less clear. In many circumstances it is difficult to
distinguish the effects of CD28 from subsequent actions of cytokines,
such as IL-2, on T cell proliferation. Here, we report a model of CD28
costimulation using PMA plus the natural ligand CD80 that resulted in
very limited stimulation of IL-2, as evidenced by both cytokine
production and IL-2 promoter stimulation. Promoter assays revealed
CD28-dependent effects on both NF-
B and AP-1, but not on NF-AT or
the intact IL-2 promoter. In addition, T cell proliferation was
completely resistant to the actions of the immunosuppressant
cyclosporin A (CsA). Moreover T cell proliferation was unaffected by
the addition of blocking Abs to both IL-2 and the IL-2 receptor,
demonstrating that this form of costimulation by CD28 was independent
of IL-2. We also investigated the effects of stimulating T cell blasts
with CD80 alone and found that there was a limited requirement for IL-2
in this system. We conclude that CD28 costimulation can cause
substantial T cell proliferation in the absence of IL-2, which is
driven by a soluble factor independent of NF-AT
transactivation.
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