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,
*
Howard Hughes Medical Institute,
Department of Medicine, Section of Hematology/Oncology, and
Department of Pathology, University of Chicago, Chicago, IL 60637
CTLA-4 is expressed on T cells after activation and shares homology
with the CD28 costimulatory receptor. In contrast to CD28, CTLA-4 is
thought to be a negative regulator of T cell activation. Cross-linking
of CTLA-4 during activation of peripheral T cells reduces IL-2
production and arrests T cells in G1. Much less is known about the
function of CTLA-4 in differentiated T cells. We have investigated the
expression and function of CTLA-4 in established Th1 and Th2 clones and
in bulk populations of Th1 and Th2 cells freshly derived in vitro from
TCR transgenic splenocytes. We found that CTLA-4 was induced under
similar conditions and with similar kinetics following activation of
both Th1 and Th2 clones. However, CTLA-4 expression was much higher in
Th2 than Th1 clones and lines. This was confirmed by flow cytometry,
confocal microscopy, and Northern blot analysis. The ratio of surface
to intracellular expression of CTLA-4 and its rate of endocytosis were
similar in Th1 and Th2 clones. Inhibition of binding of CTLA-4 to its
ligands using soluble anti-CTLA-4 mAb during stimulation with Ag
increased the production not only of IL-2 by Th1 clones, but also that
of IL-3 and IFN-
by Th1 clones and of IL-3, IL-4, IL-5, and IL-10 by
Th2 clones. In contrast, when anti-CTLA-4 was coimmobilized with
anti-CD3 and anti-CD28 mAbs, a decrease in the production of
multiple cytokines was observed. We conclude that CTLA-4 can function
to suppress the production of cytokines produced by both Th1 and Th2
cells.
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