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in the Generation and Expansion of CD4+CD25+ Regulatory T Cells from Human Peripheral Blood1
Division of Rheumatology and Immunology, University of Southern California, Keck School of Medicine, Los Angeles, CA 90033
An elusive goal in transplanting organs across histocompatibility
barriers has been the induction of specific tolerance to avoid graft
rejection. A considerable body of evidence exists that the thymus
produces regulatory T cells that suppress the response of other T cells
to antigenic stimulation. We report that TGF-
can induce certain
CD4+ T cells in the naive
(CD45RA+RO-) fraction in human peripheral
blood to develop powerful, contact-dependent suppressive activity that
is not antagonized by anti-TGF- or anti-IL-10 mAbs. The
costimulatory effects of TGF- on naive CD4+ T cells
up-regulated CD25 and CTLA-4 expression, increased their transition to
the activated phenotype, but decreased activation-induced apoptosis.
Suppressive activity was concentrated in the CD25+
fraction. These CD4+CD25+ regulatory cells
prevented CD8+ T cells from proliferating in response to
alloantigens and from becoming cytotoxic effector cells. Moreover,
these regulatory cells exerted their suppressive activities in
remarkably low numbers and maintained these effects even after they are
expanded. Once activated, their suppressive properties were Ag
nonspecific. Although <1% of naive CD4+ T cells expressed
CD25, depletion of this subset before priming with TGF- markedly
decreased the generation of suppressive activity. This finding suggests
that CD4+CD25+ regulatory T cells induced ex
vivo are the progeny of thymus-derived regulatory T cells bearing a
similar phenotype. The adoptive transfer of these regulatory T cells
generated and expanded ex vivo has the potential to prevent rejection
of allogeneic organ grafts.
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T. R. Malek The ma |
